Evidence-Based Reviews

After 10 years of heroin dependence, Mr. T, age 36, calls your office and says, “I want to get off heroin.” For 8 months, he’s been using IV heroin 2 to 3 times daily. He says he has tried methadone treatment but found daily dosing cumbersome.

He found your office number on the Substance Abuse and Mental Health Services Administration Web site, which lists physicians qualified to prescribe buprenorphine for opiate detoxification. He has heard about “bup” on the street and wants to know if he is eligible and what he can expect from treatment.

Like Mr. T, 1 million Americans are addicted to opiates.¹ As qualified physicians gain experience with using buprenorphine, this agent could revolutionize how opiate-dependent patients are routinely treated. Instead of receiving methadone only in specialized clinics, they can now choose to be treated in physicians’ offices.

Several obstacles, however, are preventing widespread buprenorphine use:

• Too few physicians are trained to offer this office-based treatment.
• Many of the 2,000 doctors who are trained remain uncertain about using buprenorphine.

This article is intended to help overcome obstacles to opiate-dependence treatment by familiarizing psychiatrists—whether trained or not in using buprenorphine—with evidence of this agent’s efficacy and its advantages compared with other treatments.

Efficacy and obstacles

Buprenorphine is a partial opioid agonist that binds to the mu receptor (Box 1).^2-5 It is a controlled substance (schedule-III narcotic). Outpatient trials have shown that buprenorphine is more effective than placebo and as effective as methadone for opiate detoxification.^6-10

In one of the largest trials, 326 opiate-dependent outpatients were randomly assigned to buprenorphine, buprenorphine/naloxone combination, or placebo for 4 weeks. Both buprenorphine forms were more effective than placebo, as measured by clean urine samples and patient reports of reduced opiate cravings.⁷

In maintenance treatment, buprenorphine has been shown to be more effective than placebo and as effective as methadone, 60 mg/d, in preventing relapse. In a randomized comparison study, 220 opiate-dependent patients received levomethadyl acetate (LAAM), 75 to 115 mg three times a week; buprenorphine, 16 to 32 mg three times a week; high-dose methadone (60 to 100 mg/d); or low-dose methadone (20 mg/d). Subjects reported using opiates 20 to 30 times in the week before study enrollment. After 17 weeks, treatment retention rates were 58% for buprenorphine, 73% for high-dose methadone, and 20% for low-dose methadone. At the same point, urine samples were negative for opiate use in 40% of patients receiving buprenorphine compared with 39% of those receiving high-dose methadone.¹⁰

Box 1

Table

Buprenorphine: A typical dosing strategy

Slow adoption. Opiate-dependence treatments such as methadone are prescribed in highly regulated environments, which is one reason only 25% of opiate addicts in the United States ever receive treatment.¹ Unfortunately, little has changed in the 20 months since the FDA approved buprenorphine for office-based detoxification and maintenance treatment of opiate dependence. More than 2,000 physicians have been trained to use buprenorphine, yet only 20% of them report prescribing it.¹¹

Reasons for this slow introduction include:

• difficulty in obtaining the medication
• lack of appropriate support staff and facilities
• uncertainty about prescribing the medication, despite special training.

Availability. When buprenorphine came to market in late 2003, most commercial pharmacies were not stocking it and it had to be special-ordered. As a result, patients receiving prescriptions had to wait 2 to 3 days for their first dose—a substantial deterrent to prescribing or taking this type of medication. Also, some private physicians and clinics do not keep buprenorphine samples to dispense on-site.

More pharmacies are stocking the medication now, but it remains the physician’s responsibility to ensure that a supply can be dispensed the day it is prescribed.

Support staff and facilities. To prescribe buprenorphine effectively, the physician needs resources for urine testing, physical exams, lab testing, and storing and dispensing buprenorphine. An integrated treatment clinic for opiate-dependent patients, complete with nursing and administrative staff, is ideal. If this support is not available, however, clinicians in private practice can safely prescribe buprenorphine from the office.

Uncertainty. Physicians often adopt new prescription products without hesitation, but buprenorphine’s administration and patient population are unusual. Even some physicians who have taken the special training course remain anxious about using this agent because it may precipitate opiate withdrawal. Also, the training requirement creates a sense that specialist-level knowledge is needed to safely prescribe buprenorphine.

Treatment requirements

For clinicians. The Drug Addiction Treatment Act of 2000 allows physicians to apply for a waiver from the Controlled Substances Act to prescribe buprenorphine for detoxification. A waiver is not required to prescribe buprenorphine for pain.¹²

To qualify for the waiver, physicians must be board-certified in addiction psychiatry or have completed a buprenorphine training course. Training is offered online and as a 1-day conference by the American Society of Addiction Medicine, American Academy of Addiction Psychiatry, American Medical Association, and American Psychiatric Association.

For patients. Like Mr. T, opiate users who ask about buprenorphine will want to know what to expect from treatment. To be eligible for buprenorphine treatment, a patient must:

• meet criteria for opiate dependence
• commit to keeping regular appointments—at least 3 times a week for the first 2 weeks then usually once weekly until detoxification is complete
• undergo random urine testing
• participate in psychosocial treatments.

So far, patients’ awareness of buprenorphine is highly variable. Asking an opiate user who presents for treatment what he or she knows about buprenorphine can be a useful screening tool. Highly motivated patients will have read about buprenorphine on the Internet, where they probably obtained your office phone number.

When a patient is accepted into treatment, detoxification with buprenorphine includes three phases: induction, stabilization/mainte-nance, and discontinuation.¹³ After stabilization, some patients remain in maintenance indefinitely and choose not to discontinue buprenorphine. The choice of who to discontinue and who to maintain on buprenorphine is a clinical decision made by the patient and practitioner. Success rates of detoxification with buprenorphine are similar to rates achieved with methadone and clonidine, although most studies have been conducted during buprenorphine maintenance.⁵

Case continued: Surprised to feel ‘normal’

Mr. T qualified for buprenorphine and came to the office feeling fairly ill. During withdrawal, his usual first symptom is rhinorrhea, followed by malaise, myalgia, restlessness, and intense cravings. His score of 24 on the Clinical Opiate Withdrawal Scale (COWS), indicated moderate withdrawal.

He felt better but not completely well 1 hour after taking buprenorphine/naloxone, 4 mg. He was given a 4-mg tablet to take at home 2 hours later. The next day his COWS score was 8, indicating mild withdrawal. He said he was surprised at how “normal” he was feeling.

Induction: Getting started

Buprenorphine induction is usually done during mild to moderate opiate withdrawal. Starting buprenorphine too soon—while the patient is relatively comfortable—may precipitate withdrawal because the agent will rapidly displace opiate bound to the receptors. In most cases, the first dose is given in the office so that the patient’s response can be monitored.

Two formulations. Buprenorphine comes alone (in 2- or 8-mg tablets) or in combination with naloxone (in 2 mg/0.5 mg and 8 mg/2 mg tablets). Both forms are given sublingually. Contrary to popular belief, IM buprenorphine is not approved for treating opiate addiction.

Naloxone is not absorbed in sublingual form and serves only to deter IV diversion of buprenorphine. Induction with buprenorphine alone is reserved for patients with documented allergy to naloxone or who are being detoxified from long-acting opiates such as methadone.

Dosing strategies are identical for both formulations. The usual starting dosage is 4 mg once daily, with a maximum dosage of 32 mg/d (Table). Withdrawal symptoms are typically controlled with 12 to 24 mg/d.¹⁴

If the patient is in active opiate withdrawal, the starting dose usually relieves symptoms in 30 to 45 minutes. If not, a second 4-mg dose can be given. Most patients do not require >8 mg the first day, but some may require 16 to 24 mg to suppress withdrawal symptoms.¹⁵

Some clinicians—such as solo practitioners who lack the resources of an outpatient clinic—prefer to have the patient take the first dose at home. Patients are instructed to take the first dose after withdrawal symptoms begin and to repeat the dose in 1 hour if symptoms persist. Thus, patients titrate their own dosages, but the clinician must be immediately available to handle complications. Induction continues until withdrawal symptoms are controlled.

The next day, patients return for evaluation. An objective scale such as the 11-item COWS can quantify withdrawal symptom severity.¹⁶ For each symptom—heart rate, nausea, diaphoresis, or restlessness—the COWS assigns a number corresponding to its severity. A total score >25 indicates moderately severe withdrawal.

After withdrawal symptoms are controlled, follow-up visits are scheduled every 2 to 3 days the first week and then weekly. Some physicians maintain daily contact with patients via e-mail or telephone to track symptoms.

Case continued: Steady improvement

By day 3, Mr. T gradually increased his buprenorphine/naloxone dosage to 16 mg once daily. He continued that dosage for 10 days before his next visit. At that point, he was slightly anxious but physically comfortable. He came into the office on days 2, 5, and 10 and his COWS scores decreased each time.

Stabilization and maintenance

When withdrawal symptoms are stabilized, patients begin maintenance therapy at the dosage that stabilized their symptoms. During maintenance therapy, the average buprenorphine dosage is 16 to 24 mg/d. Because of its long half-life, buprenorphine can be taken once daily, though some patients prefer twice-daily dosing for psychological comfort. Several studies comparing buprenorphine with methadone have found that buprenorphine, 8 to 16 mg/d, is similar in effect to approximately 60 mg/d of methadone.⁵

During the maintenance phase, it is important to have a policy for patients who relapse to substance abuse while taking buprenorphine (Box 2). During buprenorphine maintenance treatment, the estimated relapse rate to opiate use (chance of one positive test for opiates) ranges from 20% to 60%, compared with a relapse rate of 80% to 90% seen with placebo during clinical trials.⁵

Case continued: Time to taper?

After taking buprenorphine 2 months, Mr. T wants to taper off. He has been seen weekly and receives individual psychotherapy and group counseling. All urine drug screens have been negative for opiates.

With the psychiatrist’s observation, Mr. T. begins to taper his dosage of 16 mg/d by 4 mg a week. He is comfortable when he reaches 4 mg/d, but notices increased anxiety and general achiness when he reduces buprenorphine to 2 mg/d. He elects to remain at 4 mg/d for another 2 months.

Discontinuation

After the patient has reached a stable dose of buprenorphine, the clinician and patient together consider two treatment options:

• sustain the dose as maintenance therapy
• or taper and discontinue buprenorphine.

Box 2

Patients who have had multiple relapses and endured severe opiate withdrawal might consider remaining on buprenorphine for several months before tapering. Mild opiate withdrawal may occur if buprenorphine is tapered too rapidly, though this is not as severe or distressing as a full agonist withdrawal.

Tapering recommendations. To taper buprenorphine, reduce by 2 to 4 mg every 3 to 5 days until the patient is taking 2 mg/d. Most patients remain on this dosage at least 1 week and then discontinue. Those who experience side effects when dropping from 2 mg to 0 mg can take 2 mg every other day for 1 week and then discontinue.

After patients are tapered completely off buprenorphine, encourage them to follow up with the treating physician for at least another month. Opiate withdrawal symptoms have been reported to linger 2 to 3 weeks after the last dose of buprenorphine, but these symptoms—usually anxiety or insomnia—tend to be self-limiting.⁵

Case continued: Time to taper?

Mr. T has been free from heroin use for 4 months and has returned to work. He is rebuilding his life and continues with psychotherapy. He follows up at the buprenorphine clinic monthly for medication management. At each visit, he repeats the COWS test and undergoes a urine drug screen and vital signs check.

Related resources

• Substance Abuse and Mental Health Services Administration. Physician locator for buprenorphine providers.
• American Academy of Addiction Psychiatry. Information about buprenorphine training course. www.aaap.org/buprenorphine/buprenorphine.html
• Buprenorphine manufacturer’s Web site. Answers to frequently-asked questions. www.suboxone.com

Drug brand names

• Buprenorphine • Subutex
• Buprenorphine/naloxone • Suboxone
• Buprenorphine (IM) • Buprenex
• Clonidine • Catapres

After 10 years of heroin dependence, Mr. T, age 36, calls your office and says, “I want to get off heroin.” For 8 months, he’s been using IV heroin 2 to 3 times daily. He says he has tried methadone treatment but found daily dosing cumbersome.

He found your office number on the Substance Abuse and Mental Health Services Administration Web site, which lists physicians qualified to prescribe buprenorphine for opiate detoxification. He has heard about “bup” on the street and wants to know if he is eligible and what he can expect from treatment.

Like Mr. T, 1 million Americans are addicted to opiates.¹ As qualified physicians gain experience with using buprenorphine, this agent could revolutionize how opiate-dependent patients are routinely treated. Instead of receiving methadone only in specialized clinics, they can now choose to be treated in physicians’ offices.

Several obstacles, however, are preventing widespread buprenorphine use:

• Too few physicians are trained to offer this office-based treatment.
• Many of the 2,000 doctors who are trained remain uncertain about using buprenorphine.

This article is intended to help overcome obstacles to opiate-dependence treatment by familiarizing psychiatrists—whether trained or not in using buprenorphine—with evidence of this agent’s efficacy and its advantages compared with other treatments.

Efficacy and obstacles

Buprenorphine is a partial opioid agonist that binds to the mu receptor (Box 1).^2-5 It is a controlled substance (schedule-III narcotic). Outpatient trials have shown that buprenorphine is more effective than placebo and as effective as methadone for opiate detoxification.^6-10

In one of the largest trials, 326 opiate-dependent outpatients were randomly assigned to buprenorphine, buprenorphine/naloxone combination, or placebo for 4 weeks. Both buprenorphine forms were more effective than placebo, as measured by clean urine samples and patient reports of reduced opiate cravings.⁷

In maintenance treatment, buprenorphine has been shown to be more effective than placebo and as effective as methadone, 60 mg/d, in preventing relapse. In a randomized comparison study, 220 opiate-dependent patients received levomethadyl acetate (LAAM), 75 to 115 mg three times a week; buprenorphine, 16 to 32 mg three times a week; high-dose methadone (60 to 100 mg/d); or low-dose methadone (20 mg/d). Subjects reported using opiates 20 to 30 times in the week before study enrollment. After 17 weeks, treatment retention rates were 58% for buprenorphine, 73% for high-dose methadone, and 20% for low-dose methadone. At the same point, urine samples were negative for opiate use in 40% of patients receiving buprenorphine compared with 39% of those receiving high-dose methadone.¹⁰

Box 1

Table

Buprenorphine: A typical dosing strategy

Slow adoption. Opiate-dependence treatments such as methadone are prescribed in highly regulated environments, which is one reason only 25% of opiate addicts in the United States ever receive treatment.¹ Unfortunately, little has changed in the 20 months since the FDA approved buprenorphine for office-based detoxification and maintenance treatment of opiate dependence. More than 2,000 physicians have been trained to use buprenorphine, yet only 20% of them report prescribing it.¹¹

Reasons for this slow introduction include:

• difficulty in obtaining the medication
• lack of appropriate support staff and facilities
• uncertainty about prescribing the medication, despite special training.

Availability. When buprenorphine came to market in late 2003, most commercial pharmacies were not stocking it and it had to be special-ordered. As a result, patients receiving prescriptions had to wait 2 to 3 days for their first dose—a substantial deterrent to prescribing or taking this type of medication. Also, some private physicians and clinics do not keep buprenorphine samples to dispense on-site.

More pharmacies are stocking the medication now, but it remains the physician’s responsibility to ensure that a supply can be dispensed the day it is prescribed.

Support staff and facilities. To prescribe buprenorphine effectively, the physician needs resources for urine testing, physical exams, lab testing, and storing and dispensing buprenorphine. An integrated treatment clinic for opiate-dependent patients, complete with nursing and administrative staff, is ideal. If this support is not available, however, clinicians in private practice can safely prescribe buprenorphine from the office.

Uncertainty. Physicians often adopt new prescription products without hesitation, but buprenorphine’s administration and patient population are unusual. Even some physicians who have taken the special training course remain anxious about using this agent because it may precipitate opiate withdrawal. Also, the training requirement creates a sense that specialist-level knowledge is needed to safely prescribe buprenorphine.

Treatment requirements

For clinicians. The Drug Addiction Treatment Act of 2000 allows physicians to apply for a waiver from the Controlled Substances Act to prescribe buprenorphine for detoxification. A waiver is not required to prescribe buprenorphine for pain.¹²

To qualify for the waiver, physicians must be board-certified in addiction psychiatry or have completed a buprenorphine training course. Training is offered online and as a 1-day conference by the American Society of Addiction Medicine, American Academy of Addiction Psychiatry, American Medical Association, and American Psychiatric Association.

For patients. Like Mr. T, opiate users who ask about buprenorphine will want to know what to expect from treatment. To be eligible for buprenorphine treatment, a patient must:

• meet criteria for opiate dependence
• commit to keeping regular appointments—at least 3 times a week for the first 2 weeks then usually once weekly until detoxification is complete
• undergo random urine testing
• participate in psychosocial treatments.

So far, patients’ awareness of buprenorphine is highly variable. Asking an opiate user who presents for treatment what he or she knows about buprenorphine can be a useful screening tool. Highly motivated patients will have read about buprenorphine on the Internet, where they probably obtained your office phone number.

When a patient is accepted into treatment, detoxification with buprenorphine includes three phases: induction, stabilization/mainte-nance, and discontinuation.¹³ After stabilization, some patients remain in maintenance indefinitely and choose not to discontinue buprenorphine. The choice of who to discontinue and who to maintain on buprenorphine is a clinical decision made by the patient and practitioner. Success rates of detoxification with buprenorphine are similar to rates achieved with methadone and clonidine, although most studies have been conducted during buprenorphine maintenance.⁵

Case continued: Surprised to feel ‘normal’

Mr. T qualified for buprenorphine and came to the office feeling fairly ill. During withdrawal, his usual first symptom is rhinorrhea, followed by malaise, myalgia, restlessness, and intense cravings. His score of 24 on the Clinical Opiate Withdrawal Scale (COWS), indicated moderate withdrawal.

He felt better but not completely well 1 hour after taking buprenorphine/naloxone, 4 mg. He was given a 4-mg tablet to take at home 2 hours later. The next day his COWS score was 8, indicating mild withdrawal. He said he was surprised at how “normal” he was feeling.

Induction: Getting started

Buprenorphine induction is usually done during mild to moderate opiate withdrawal. Starting buprenorphine too soon—while the patient is relatively comfortable—may precipitate withdrawal because the agent will rapidly displace opiate bound to the receptors. In most cases, the first dose is given in the office so that the patient’s response can be monitored.

Two formulations. Buprenorphine comes alone (in 2- or 8-mg tablets) or in combination with naloxone (in 2 mg/0.5 mg and 8 mg/2 mg tablets). Both forms are given sublingually. Contrary to popular belief, IM buprenorphine is not approved for treating opiate addiction.

Naloxone is not absorbed in sublingual form and serves only to deter IV diversion of buprenorphine. Induction with buprenorphine alone is reserved for patients with documented allergy to naloxone or who are being detoxified from long-acting opiates such as methadone.

Dosing strategies are identical for both formulations. The usual starting dosage is 4 mg once daily, with a maximum dosage of 32 mg/d (Table). Withdrawal symptoms are typically controlled with 12 to 24 mg/d.¹⁴

If the patient is in active opiate withdrawal, the starting dose usually relieves symptoms in 30 to 45 minutes. If not, a second 4-mg dose can be given. Most patients do not require >8 mg the first day, but some may require 16 to 24 mg to suppress withdrawal symptoms.¹⁵

Some clinicians—such as solo practitioners who lack the resources of an outpatient clinic—prefer to have the patient take the first dose at home. Patients are instructed to take the first dose after withdrawal symptoms begin and to repeat the dose in 1 hour if symptoms persist. Thus, patients titrate their own dosages, but the clinician must be immediately available to handle complications. Induction continues until withdrawal symptoms are controlled.

The next day, patients return for evaluation. An objective scale such as the 11-item COWS can quantify withdrawal symptom severity.¹⁶ For each symptom—heart rate, nausea, diaphoresis, or restlessness—the COWS assigns a number corresponding to its severity. A total score >25 indicates moderately severe withdrawal.

After withdrawal symptoms are controlled, follow-up visits are scheduled every 2 to 3 days the first week and then weekly. Some physicians maintain daily contact with patients via e-mail or telephone to track symptoms.

Case continued: Steady improvement

By day 3, Mr. T gradually increased his buprenorphine/naloxone dosage to 16 mg once daily. He continued that dosage for 10 days before his next visit. At that point, he was slightly anxious but physically comfortable. He came into the office on days 2, 5, and 10 and his COWS scores decreased each time.

Stabilization and maintenance

When withdrawal symptoms are stabilized, patients begin maintenance therapy at the dosage that stabilized their symptoms. During maintenance therapy, the average buprenorphine dosage is 16 to 24 mg/d. Because of its long half-life, buprenorphine can be taken once daily, though some patients prefer twice-daily dosing for psychological comfort. Several studies comparing buprenorphine with methadone have found that buprenorphine, 8 to 16 mg/d, is similar in effect to approximately 60 mg/d of methadone.⁵

During the maintenance phase, it is important to have a policy for patients who relapse to substance abuse while taking buprenorphine (Box 2). During buprenorphine maintenance treatment, the estimated relapse rate to opiate use (chance of one positive test for opiates) ranges from 20% to 60%, compared with a relapse rate of 80% to 90% seen with placebo during clinical trials.⁵

Case continued: Time to taper?

After taking buprenorphine 2 months, Mr. T wants to taper off. He has been seen weekly and receives individual psychotherapy and group counseling. All urine drug screens have been negative for opiates.

With the psychiatrist’s observation, Mr. T. begins to taper his dosage of 16 mg/d by 4 mg a week. He is comfortable when he reaches 4 mg/d, but notices increased anxiety and general achiness when he reduces buprenorphine to 2 mg/d. He elects to remain at 4 mg/d for another 2 months.

Discontinuation

After the patient has reached a stable dose of buprenorphine, the clinician and patient together consider two treatment options:

• sustain the dose as maintenance therapy
• or taper and discontinue buprenorphine.

Box 2

Patients who have had multiple relapses and endured severe opiate withdrawal might consider remaining on buprenorphine for several months before tapering. Mild opiate withdrawal may occur if buprenorphine is tapered too rapidly, though this is not as severe or distressing as a full agonist withdrawal.

Tapering recommendations. To taper buprenorphine, reduce by 2 to 4 mg every 3 to 5 days until the patient is taking 2 mg/d. Most patients remain on this dosage at least 1 week and then discontinue. Those who experience side effects when dropping from 2 mg to 0 mg can take 2 mg every other day for 1 week and then discontinue.

After patients are tapered completely off buprenorphine, encourage them to follow up with the treating physician for at least another month. Opiate withdrawal symptoms have been reported to linger 2 to 3 weeks after the last dose of buprenorphine, but these symptoms—usually anxiety or insomnia—tend to be self-limiting.⁵

Case continued: Time to taper?

Mr. T has been free from heroin use for 4 months and has returned to work. He is rebuilding his life and continues with psychotherapy. He follows up at the buprenorphine clinic monthly for medication management. At each visit, he repeats the COWS test and undergoes a urine drug screen and vital signs check.

Related resources

• Substance Abuse and Mental Health Services Administration. Physician locator for buprenorphine providers.
• American Academy of Addiction Psychiatry. Information about buprenorphine training course. www.aaap.org/buprenorphine/buprenorphine.html
• Buprenorphine manufacturer’s Web site. Answers to frequently-asked questions. www.suboxone.com

Drug brand names

• Buprenorphine • Subutex
• Buprenorphine/naloxone • Suboxone
• Buprenorphine (IM) • Buprenex
• Clonidine • Catapres

After 10 years of heroin dependence, Mr. T, age 36, calls your office and says, “I want to get off heroin.” For 8 months, he’s been using IV heroin 2 to 3 times daily. He says he has tried methadone treatment but found daily dosing cumbersome.

He found your office number on the Substance Abuse and Mental Health Services Administration Web site, which lists physicians qualified to prescribe buprenorphine for opiate detoxification. He has heard about “bup” on the street and wants to know if he is eligible and what he can expect from treatment.

Like Mr. T, 1 million Americans are addicted to opiates.¹ As qualified physicians gain experience with using buprenorphine, this agent could revolutionize how opiate-dependent patients are routinely treated. Instead of receiving methadone only in specialized clinics, they can now choose to be treated in physicians’ offices.

Several obstacles, however, are preventing widespread buprenorphine use:

• Too few physicians are trained to offer this office-based treatment.
• Many of the 2,000 doctors who are trained remain uncertain about using buprenorphine.

This article is intended to help overcome obstacles to opiate-dependence treatment by familiarizing psychiatrists—whether trained or not in using buprenorphine—with evidence of this agent’s efficacy and its advantages compared with other treatments.

Efficacy and obstacles

Buprenorphine is a partial opioid agonist that binds to the mu receptor (Box 1).^2-5 It is a controlled substance (schedule-III narcotic). Outpatient trials have shown that buprenorphine is more effective than placebo and as effective as methadone for opiate detoxification.^6-10

In one of the largest trials, 326 opiate-dependent outpatients were randomly assigned to buprenorphine, buprenorphine/naloxone combination, or placebo for 4 weeks. Both buprenorphine forms were more effective than placebo, as measured by clean urine samples and patient reports of reduced opiate cravings.⁷

In maintenance treatment, buprenorphine has been shown to be more effective than placebo and as effective as methadone, 60 mg/d, in preventing relapse. In a randomized comparison study, 220 opiate-dependent patients received levomethadyl acetate (LAAM), 75 to 115 mg three times a week; buprenorphine, 16 to 32 mg three times a week; high-dose methadone (60 to 100 mg/d); or low-dose methadone (20 mg/d). Subjects reported using opiates 20 to 30 times in the week before study enrollment. After 17 weeks, treatment retention rates were 58% for buprenorphine, 73% for high-dose methadone, and 20% for low-dose methadone. At the same point, urine samples were negative for opiate use in 40% of patients receiving buprenorphine compared with 39% of those receiving high-dose methadone.¹⁰

Box 1

Table

Buprenorphine: A typical dosing strategy

Slow adoption. Opiate-dependence treatments such as methadone are prescribed in highly regulated environments, which is one reason only 25% of opiate addicts in the United States ever receive treatment.¹ Unfortunately, little has changed in the 20 months since the FDA approved buprenorphine for office-based detoxification and maintenance treatment of opiate dependence. More than 2,000 physicians have been trained to use buprenorphine, yet only 20% of them report prescribing it.¹¹

Reasons for this slow introduction include:

• difficulty in obtaining the medication
• lack of appropriate support staff and facilities
• uncertainty about prescribing the medication, despite special training.

Availability. When buprenorphine came to market in late 2003, most commercial pharmacies were not stocking it and it had to be special-ordered. As a result, patients receiving prescriptions had to wait 2 to 3 days for their first dose—a substantial deterrent to prescribing or taking this type of medication. Also, some private physicians and clinics do not keep buprenorphine samples to dispense on-site.

More pharmacies are stocking the medication now, but it remains the physician’s responsibility to ensure that a supply can be dispensed the day it is prescribed.

Support staff and facilities. To prescribe buprenorphine effectively, the physician needs resources for urine testing, physical exams, lab testing, and storing and dispensing buprenorphine. An integrated treatment clinic for opiate-dependent patients, complete with nursing and administrative staff, is ideal. If this support is not available, however, clinicians in private practice can safely prescribe buprenorphine from the office.

Uncertainty. Physicians often adopt new prescription products without hesitation, but buprenorphine’s administration and patient population are unusual. Even some physicians who have taken the special training course remain anxious about using this agent because it may precipitate opiate withdrawal. Also, the training requirement creates a sense that specialist-level knowledge is needed to safely prescribe buprenorphine.

Treatment requirements

For clinicians. The Drug Addiction Treatment Act of 2000 allows physicians to apply for a waiver from the Controlled Substances Act to prescribe buprenorphine for detoxification. A waiver is not required to prescribe buprenorphine for pain.¹²

To qualify for the waiver, physicians must be board-certified in addiction psychiatry or have completed a buprenorphine training course. Training is offered online and as a 1-day conference by the American Society of Addiction Medicine, American Academy of Addiction Psychiatry, American Medical Association, and American Psychiatric Association.

For patients. Like Mr. T, opiate users who ask about buprenorphine will want to know what to expect from treatment. To be eligible for buprenorphine treatment, a patient must:

• meet criteria for opiate dependence
• commit to keeping regular appointments—at least 3 times a week for the first 2 weeks then usually once weekly until detoxification is complete
• undergo random urine testing
• participate in psychosocial treatments.

So far, patients’ awareness of buprenorphine is highly variable. Asking an opiate user who presents for treatment what he or she knows about buprenorphine can be a useful screening tool. Highly motivated patients will have read about buprenorphine on the Internet, where they probably obtained your office phone number.

When a patient is accepted into treatment, detoxification with buprenorphine includes three phases: induction, stabilization/mainte-nance, and discontinuation.¹³ After stabilization, some patients remain in maintenance indefinitely and choose not to discontinue buprenorphine. The choice of who to discontinue and who to maintain on buprenorphine is a clinical decision made by the patient and practitioner. Success rates of detoxification with buprenorphine are similar to rates achieved with methadone and clonidine, although most studies have been conducted during buprenorphine maintenance.⁵

Case continued: Surprised to feel ‘normal’

Mr. T qualified for buprenorphine and came to the office feeling fairly ill. During withdrawal, his usual first symptom is rhinorrhea, followed by malaise, myalgia, restlessness, and intense cravings. His score of 24 on the Clinical Opiate Withdrawal Scale (COWS), indicated moderate withdrawal.

He felt better but not completely well 1 hour after taking buprenorphine/naloxone, 4 mg. He was given a 4-mg tablet to take at home 2 hours later. The next day his COWS score was 8, indicating mild withdrawal. He said he was surprised at how “normal” he was feeling.

Induction: Getting started

Buprenorphine induction is usually done during mild to moderate opiate withdrawal. Starting buprenorphine too soon—while the patient is relatively comfortable—may precipitate withdrawal because the agent will rapidly displace opiate bound to the receptors. In most cases, the first dose is given in the office so that the patient’s response can be monitored.

Two formulations. Buprenorphine comes alone (in 2- or 8-mg tablets) or in combination with naloxone (in 2 mg/0.5 mg and 8 mg/2 mg tablets). Both forms are given sublingually. Contrary to popular belief, IM buprenorphine is not approved for treating opiate addiction.

Naloxone is not absorbed in sublingual form and serves only to deter IV diversion of buprenorphine. Induction with buprenorphine alone is reserved for patients with documented allergy to naloxone or who are being detoxified from long-acting opiates such as methadone.

Dosing strategies are identical for both formulations. The usual starting dosage is 4 mg once daily, with a maximum dosage of 32 mg/d (Table). Withdrawal symptoms are typically controlled with 12 to 24 mg/d.¹⁴

If the patient is in active opiate withdrawal, the starting dose usually relieves symptoms in 30 to 45 minutes. If not, a second 4-mg dose can be given. Most patients do not require >8 mg the first day, but some may require 16 to 24 mg to suppress withdrawal symptoms.¹⁵

Some clinicians—such as solo practitioners who lack the resources of an outpatient clinic—prefer to have the patient take the first dose at home. Patients are instructed to take the first dose after withdrawal symptoms begin and to repeat the dose in 1 hour if symptoms persist. Thus, patients titrate their own dosages, but the clinician must be immediately available to handle complications. Induction continues until withdrawal symptoms are controlled.

The next day, patients return for evaluation. An objective scale such as the 11-item COWS can quantify withdrawal symptom severity.¹⁶ For each symptom—heart rate, nausea, diaphoresis, or restlessness—the COWS assigns a number corresponding to its severity. A total score >25 indicates moderately severe withdrawal.

After withdrawal symptoms are controlled, follow-up visits are scheduled every 2 to 3 days the first week and then weekly. Some physicians maintain daily contact with patients via e-mail or telephone to track symptoms.

Case continued: Steady improvement

By day 3, Mr. T gradually increased his buprenorphine/naloxone dosage to 16 mg once daily. He continued that dosage for 10 days before his next visit. At that point, he was slightly anxious but physically comfortable. He came into the office on days 2, 5, and 10 and his COWS scores decreased each time.

Stabilization and maintenance

When withdrawal symptoms are stabilized, patients begin maintenance therapy at the dosage that stabilized their symptoms. During maintenance therapy, the average buprenorphine dosage is 16 to 24 mg/d. Because of its long half-life, buprenorphine can be taken once daily, though some patients prefer twice-daily dosing for psychological comfort. Several studies comparing buprenorphine with methadone have found that buprenorphine, 8 to 16 mg/d, is similar in effect to approximately 60 mg/d of methadone.⁵

During the maintenance phase, it is important to have a policy for patients who relapse to substance abuse while taking buprenorphine (Box 2). During buprenorphine maintenance treatment, the estimated relapse rate to opiate use (chance of one positive test for opiates) ranges from 20% to 60%, compared with a relapse rate of 80% to 90% seen with placebo during clinical trials.⁵

Case continued: Time to taper?

After taking buprenorphine 2 months, Mr. T wants to taper off. He has been seen weekly and receives individual psychotherapy and group counseling. All urine drug screens have been negative for opiates.

With the psychiatrist’s observation, Mr. T. begins to taper his dosage of 16 mg/d by 4 mg a week. He is comfortable when he reaches 4 mg/d, but notices increased anxiety and general achiness when he reduces buprenorphine to 2 mg/d. He elects to remain at 4 mg/d for another 2 months.

Discontinuation

After the patient has reached a stable dose of buprenorphine, the clinician and patient together consider two treatment options:

• sustain the dose as maintenance therapy
• or taper and discontinue buprenorphine.

Box 2

Patients who have had multiple relapses and endured severe opiate withdrawal might consider remaining on buprenorphine for several months before tapering. Mild opiate withdrawal may occur if buprenorphine is tapered too rapidly, though this is not as severe or distressing as a full agonist withdrawal.

Tapering recommendations. To taper buprenorphine, reduce by 2 to 4 mg every 3 to 5 days until the patient is taking 2 mg/d. Most patients remain on this dosage at least 1 week and then discontinue. Those who experience side effects when dropping from 2 mg to 0 mg can take 2 mg every other day for 1 week and then discontinue.

After patients are tapered completely off buprenorphine, encourage them to follow up with the treating physician for at least another month. Opiate withdrawal symptoms have been reported to linger 2 to 3 weeks after the last dose of buprenorphine, but these symptoms—usually anxiety or insomnia—tend to be self-limiting.⁵

Case continued: Time to taper?

Mr. T has been free from heroin use for 4 months and has returned to work. He is rebuilding his life and continues with psychotherapy. He follows up at the buprenorphine clinic monthly for medication management. At each visit, he repeats the COWS test and undergoes a urine drug screen and vital signs check.

Related resources

• Substance Abuse and Mental Health Services Administration. Physician locator for buprenorphine providers.
• American Academy of Addiction Psychiatry. Information about buprenorphine training course. www.aaap.org/buprenorphine/buprenorphine.html
• Buprenorphine manufacturer’s Web site. Answers to frequently-asked questions. www.suboxone.com

Drug brand names

• Buprenorphine • Subutex
• Buprenorphine/naloxone • Suboxone
• Buprenorphine (IM) • Buprenex
• Clonidine • Catapres

Ms. H, age 26, is being evaluated for moderate to severe depressive symptoms, including oversleeping and overeating. She has had difficulty adhering to medication in the past and is ambivalent about taking antidepressants. She takes a passive approach to managing her depression, preferring to “wait for it to pass.”

Her psychiatrist prescribes fluoxetine, 20 mg in the morning, and recommends that Ms. H change her coping strategies from napping and snacking to increased physical activity. She encourages Ms. H to think about what activities interest her and to set exercise goals.

Ms. H says she has considered buying exercise equipment (an elliptical machine) and increasing her walking outside. She sets a goal to walk 20 minutes most days and to spend 10 to 15 minutes using the elliptical machine while watching television.

Physical activity’s mental health benefits are less well-known than its well-documented medical benefits—reduced risk of heart disease, hypertension, and diabetes; weight control; bone mass preservation; better sleep, and improved cholesterol levels.¹ By encouraging exercise, you can improve patients’ mood, well-being, and quality of life, independent of medication and psychotherapy. In this article, we:

• explore the relationship between physical activity and mental health
• compare exercise with medication and psychotherapies for easing depression
• discuss counseling strategies shown to be effective in helping sedentary patients become more physically active.

Table 1

Why physical activity may improve mental health

Mental benefits of exercise

Adults who exercise regularly report lower levels of depressive and anxiety disorders than the overall U.S. population.² As a therapeutic intervention, exercise has been studied primarily in depressed individuals, although some data also support its efficacy in:

• reducing anxiety symptoms in panic disorder³
• reducing disruptive behavior in developmentally disabled patients⁴
• alleviating chronic fatigue symptoms⁵
• improving body esteem in patients with body image disturbance⁶
• increasing function in chronic pain⁷
• reducing urges to smoke and improving smoking abstinence among nicotine-dependent individuals.⁸

Why exercise helps. Mechanisms that would explain exercise’s positive effect on mood are not well understood.⁹ Physiologic and psychological hypotheses have been suggested (Table 1),^10,11 and researchers are attempting to elucidate them by using animal models.¹³

Case report: Feeling more energetic

At follow-up 6 weeks later, Ms. H. reported a substantial reduction in depressive symptoms. She noted increased energy, improved sleep, decreased overeating, higher self-esteem, and greater confidence in her ability to manage her depression.

Exercising also helped structure her day. She noticed that on days she did not exercise she was more likely to take a nap, miss her medication, or feel pessimistic about her depression.

Exercise as an antidepressant

Exercise vs psychotherapy. Exercise has been shown to be more effective at reducing depressive symptoms than no treatment, occupational therapy, cognitive therapy, health seminars, routine care, or meditation. Interventions used in these meta-analyses ranged from nonaerobic exercise training several times a week to 1 hour of supervised running 4 times a week.¹² Literature reviews also have concluded that exercise training compares favorably with individual or group psychotherapy and with cognitive therapy for treating depression.⁷

Exercise vs medication. Exercise training has also been compared with drug therapy in treating depression.

In a randomized, controlled trial, 156 men and women over age 50 with major depression received exercise training, sertraline, or exercise plus sertraline. Subjects in the exercise groups completed 40 minutes of aerobic exercise (biking or brisk walking/ jogging) 3 times a week. Subjects treated with sertraline received 50 to 200 mg/d, depending on response.

After 16 weeks, all three groups were significantly improved, with no clinically or statistically significant differences in depressive symptoms, as measured with the Hamilton Rating Scale for Depression (HRSD) and Beck Depression Inventory.¹³

In a follow-up study 6 months later,¹⁴ the exercise group had significantly lower rates of relapse (defined as HRSD scores >15 and meeting diagnostic criteria) than did the medication group. Combining exercise with medication did not provide an added benefit in preventing relapse.

Exercise as monotherapy. Some studies have investigated using exercise instead of medication and psychotherapy. Many of these trials, however, were limited by methodologic weaknesses such as nonrandomized samples or lack of appropriate control groups.¹²

To address the need for higher-quality evidence, the Depression Outcomes Study of Exercise (DOSE) is investigating the dose-continued from page 12 response effects of exercise as monotherapy for major depressive disorder (MDD).⁵ The 12-week trial included 80 men and women ages 20 to 45 diagnosed with mild-to-moderate MDD using the Structured Clinical Interview for Depression. They were randomly assigned to one of five supervised exercise regimens:

• 7.0 kcal/kg/week in 3 days/week
• 7.0 kcal/kg/week in 5 days/week
• 17.5 kcal/kg/week in 3 days/week
• 17.5 kcal/kg/week in 5 days/week
• 3 days/week of stretching and flexibility exercises for 15 to 20 min/session.

Table 2

How much physical activity is recommended for adults?

Depressive symptoms were measured with the HRSD and Inventory of Depressive Symptoms (clinician and self-report). Other outcome measures included cardiorespiratory fitness, self-efficacy, and quality of life. Results are being prepared for publication and will likely help clarify the role of physical activity in treating patients with MDD.

Table 3

Why patients don’t exercise: Common barriers they perceive

How much exercise is therapeutic?

In the absence of physical activity guidelines specific to mental health, we suggest using standard public health guidelines (Table 2):

• 30 minutes or more of moderate-intensity physical activity (brisk walking, swimming, dancing, cycling) most days of the week (recommended by the Centers for Disease Control and Prevention and American College of Sports Medicine)¹
• 60 minutes of moderate-intensity physical activity daily for weight loss and maintenance (recommended by the Institute of Medicine).¹⁶

A recent study investigated the effects of exercise duration and intensity on weight loss in overweight, sedentary women. These researchers recommended setting the initial intervention target at 150 minutes or more of moderate-intensity exercise per week and progressing to 60 minutes per day as appropriate.¹⁶

Increasing the number of steps taken per day, as measured by a pedometer, also can be beneficial. Encourage patients to obtain a baseline measure of daily steps and to gradually increase toward a moderate goal of 10,000 steps per day.¹⁷

Case report: Accentuating the positive

On follow-up, Ms. H was quick to report the many barriers to exercise she had experienced and the times she did not meet her goal. Rather than dwell on shortcomings, the psychiatrist redirected her to examine the many positive actions she had taken to manage her depression.

As she considered how to overcome barriers to exercise, she reported increased confidence that she could stick with her medication and exercise regimen. She continues to exercise regularly and adheres to her fluoxetine. Her depressive symptoms remain well-controlled.

Overcoming barriers to exercise

Patient obstacles. Many patients acknowledge that regular exercise makes them feel physically and emotionally healthier but have difficulty exercising long term. Less than one-half of those who start an exercise program stick with it beyond 6 months.¹⁸ Drop-out reasons include injuries, lack of time, and low motivation (Table 3).^19,20

Depressive symptoms—fatigue, loss of interest, low self-esteem, feelings of helplessness, and psychomotor retardation—make exercise adherence even more difficult.

Physician obstacles. The U.S. Preventive Services Task Force recommends that physicians advise all patients to increase physical activity, but the national rate of physician counseling about exercise is low. In a population-based survey of more than 9,000 patients, 34% said their physicians counseled them about exercise at their most recent visit within the past year.²¹

Physician-reported barriers to exercise counseling include:

• competing demands for limited clinical time
• perceived ineffectiveness of advice to exercise
• lack of training and knowledge about exercise counseling and prescription.^22,23

Patients are more likely to become active and continue exercising when their physicians help them set achievable goals.

Project PACE. Physicians can overcome barriers to counseling patients about exercise. Those who participated in Project PACE (Physician-based Assessment and Counseling for Exercise)²⁴ said they felt more confident that they could counsel patients about physical activity in 1 to 5 minutes.

In a controlled study of 212 sedentary adults, patients who received PACE counseling from their physicians significantly increased their minutes of weekly walking compared with a control group. Also, 52% of patients who received PACE counseling adopted some physical activity, compared with 12% of controls.²⁵

Though modest initial goals are not sufficient for achieving the full benefits of exercise, success with a small goal is a powerful motivator. Rather than giving up, patients feel encouraged and are more likely to set a subsequent, more ambitious goal.

Recommendations. To help patients start exercising, determine how motivated and ready they are. Start by asking them to describe their current activities. Ask if they were ever more active and what they liked about it. Did they experience any benefits? Establish which of increased activity’s benefits—improved sleep, reduced depression, increased energy—would most benefit the patient, based on his or her symptoms.

Discuss barriers to physical activity and encourage problem-solving to overcome them and incorporate physical activity into their lives. Encourage patients to seek support from family, friends, coworkers, and exercise groups.

Help them set realistic, achievable goals. Even a modest 10 minutes of activity has been shown to enhance mood,²⁶ and a 10-minute brisk walk is one-third of the day’s public health guideline. Suggest that patients choose a variety of activities they enjoy.

During follow-up visits, reinforce any progress toward change. When patients’ exercise efforts fall short, explain that the process of becoming more active often includes setbacks. Advise them to seek support and to consider adopting more-achievable goals.

Related resources

• Getting started. Resources on nutrition and physical activity from the National Center for Chronic Disease Prevention and Health Promotion. http://www.cdc.gov/nccdphp/dnpa/physical/starting/index.htm
• Marcus B, Forsyth L. Motivating people to be physically active. Champaign, IL: Human Kinetics, 2002.

Drug brand names

• Fluoxetine • Prozac
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. H, age 26, is being evaluated for moderate to severe depressive symptoms, including oversleeping and overeating. She has had difficulty adhering to medication in the past and is ambivalent about taking antidepressants. She takes a passive approach to managing her depression, preferring to “wait for it to pass.”

Her psychiatrist prescribes fluoxetine, 20 mg in the morning, and recommends that Ms. H change her coping strategies from napping and snacking to increased physical activity. She encourages Ms. H to think about what activities interest her and to set exercise goals.

Ms. H says she has considered buying exercise equipment (an elliptical machine) and increasing her walking outside. She sets a goal to walk 20 minutes most days and to spend 10 to 15 minutes using the elliptical machine while watching television.

Physical activity’s mental health benefits are less well-known than its well-documented medical benefits—reduced risk of heart disease, hypertension, and diabetes; weight control; bone mass preservation; better sleep, and improved cholesterol levels.¹ By encouraging exercise, you can improve patients’ mood, well-being, and quality of life, independent of medication and psychotherapy. In this article, we:

• explore the relationship between physical activity and mental health
• compare exercise with medication and psychotherapies for easing depression
• discuss counseling strategies shown to be effective in helping sedentary patients become more physically active.

Table 1

Why physical activity may improve mental health

Mental benefits of exercise

Adults who exercise regularly report lower levels of depressive and anxiety disorders than the overall U.S. population.² As a therapeutic intervention, exercise has been studied primarily in depressed individuals, although some data also support its efficacy in:

• reducing anxiety symptoms in panic disorder³
• reducing disruptive behavior in developmentally disabled patients⁴
• alleviating chronic fatigue symptoms⁵
• improving body esteem in patients with body image disturbance⁶
• increasing function in chronic pain⁷
• reducing urges to smoke and improving smoking abstinence among nicotine-dependent individuals.⁸

Why exercise helps. Mechanisms that would explain exercise’s positive effect on mood are not well understood.⁹ Physiologic and psychological hypotheses have been suggested (Table 1),^10,11 and researchers are attempting to elucidate them by using animal models.¹³

Case report: Feeling more energetic

At follow-up 6 weeks later, Ms. H. reported a substantial reduction in depressive symptoms. She noted increased energy, improved sleep, decreased overeating, higher self-esteem, and greater confidence in her ability to manage her depression.

Exercising also helped structure her day. She noticed that on days she did not exercise she was more likely to take a nap, miss her medication, or feel pessimistic about her depression.

Exercise as an antidepressant

Exercise vs psychotherapy. Exercise has been shown to be more effective at reducing depressive symptoms than no treatment, occupational therapy, cognitive therapy, health seminars, routine care, or meditation. Interventions used in these meta-analyses ranged from nonaerobic exercise training several times a week to 1 hour of supervised running 4 times a week.¹² Literature reviews also have concluded that exercise training compares favorably with individual or group psychotherapy and with cognitive therapy for treating depression.⁷

Exercise vs medication. Exercise training has also been compared with drug therapy in treating depression.

In a randomized, controlled trial, 156 men and women over age 50 with major depression received exercise training, sertraline, or exercise plus sertraline. Subjects in the exercise groups completed 40 minutes of aerobic exercise (biking or brisk walking/ jogging) 3 times a week. Subjects treated with sertraline received 50 to 200 mg/d, depending on response.

After 16 weeks, all three groups were significantly improved, with no clinically or statistically significant differences in depressive symptoms, as measured with the Hamilton Rating Scale for Depression (HRSD) and Beck Depression Inventory.¹³

In a follow-up study 6 months later,¹⁴ the exercise group had significantly lower rates of relapse (defined as HRSD scores >15 and meeting diagnostic criteria) than did the medication group. Combining exercise with medication did not provide an added benefit in preventing relapse.

Exercise as monotherapy. Some studies have investigated using exercise instead of medication and psychotherapy. Many of these trials, however, were limited by methodologic weaknesses such as nonrandomized samples or lack of appropriate control groups.¹²

To address the need for higher-quality evidence, the Depression Outcomes Study of Exercise (DOSE) is investigating the dose-continued from page 12 response effects of exercise as monotherapy for major depressive disorder (MDD).⁵ The 12-week trial included 80 men and women ages 20 to 45 diagnosed with mild-to-moderate MDD using the Structured Clinical Interview for Depression. They were randomly assigned to one of five supervised exercise regimens:

• 7.0 kcal/kg/week in 3 days/week
• 7.0 kcal/kg/week in 5 days/week
• 17.5 kcal/kg/week in 3 days/week
• 17.5 kcal/kg/week in 5 days/week
• 3 days/week of stretching and flexibility exercises for 15 to 20 min/session.

Table 2

How much physical activity is recommended for adults?

Depressive symptoms were measured with the HRSD and Inventory of Depressive Symptoms (clinician and self-report). Other outcome measures included cardiorespiratory fitness, self-efficacy, and quality of life. Results are being prepared for publication and will likely help clarify the role of physical activity in treating patients with MDD.

Table 3

Why patients don’t exercise: Common barriers they perceive

How much exercise is therapeutic?

In the absence of physical activity guidelines specific to mental health, we suggest using standard public health guidelines (Table 2):

• 30 minutes or more of moderate-intensity physical activity (brisk walking, swimming, dancing, cycling) most days of the week (recommended by the Centers for Disease Control and Prevention and American College of Sports Medicine)¹
• 60 minutes of moderate-intensity physical activity daily for weight loss and maintenance (recommended by the Institute of Medicine).¹⁶

A recent study investigated the effects of exercise duration and intensity on weight loss in overweight, sedentary women. These researchers recommended setting the initial intervention target at 150 minutes or more of moderate-intensity exercise per week and progressing to 60 minutes per day as appropriate.¹⁶

Increasing the number of steps taken per day, as measured by a pedometer, also can be beneficial. Encourage patients to obtain a baseline measure of daily steps and to gradually increase toward a moderate goal of 10,000 steps per day.¹⁷

Case report: Accentuating the positive

On follow-up, Ms. H was quick to report the many barriers to exercise she had experienced and the times she did not meet her goal. Rather than dwell on shortcomings, the psychiatrist redirected her to examine the many positive actions she had taken to manage her depression.

As she considered how to overcome barriers to exercise, she reported increased confidence that she could stick with her medication and exercise regimen. She continues to exercise regularly and adheres to her fluoxetine. Her depressive symptoms remain well-controlled.

Overcoming barriers to exercise

Patient obstacles. Many patients acknowledge that regular exercise makes them feel physically and emotionally healthier but have difficulty exercising long term. Less than one-half of those who start an exercise program stick with it beyond 6 months.¹⁸ Drop-out reasons include injuries, lack of time, and low motivation (Table 3).^19,20

Depressive symptoms—fatigue, loss of interest, low self-esteem, feelings of helplessness, and psychomotor retardation—make exercise adherence even more difficult.

Physician obstacles. The U.S. Preventive Services Task Force recommends that physicians advise all patients to increase physical activity, but the national rate of physician counseling about exercise is low. In a population-based survey of more than 9,000 patients, 34% said their physicians counseled them about exercise at their most recent visit within the past year.²¹

Physician-reported barriers to exercise counseling include:

• competing demands for limited clinical time
• perceived ineffectiveness of advice to exercise
• lack of training and knowledge about exercise counseling and prescription.^22,23

Patients are more likely to become active and continue exercising when their physicians help them set achievable goals.

Project PACE. Physicians can overcome barriers to counseling patients about exercise. Those who participated in Project PACE (Physician-based Assessment and Counseling for Exercise)²⁴ said they felt more confident that they could counsel patients about physical activity in 1 to 5 minutes.

In a controlled study of 212 sedentary adults, patients who received PACE counseling from their physicians significantly increased their minutes of weekly walking compared with a control group. Also, 52% of patients who received PACE counseling adopted some physical activity, compared with 12% of controls.²⁵

Though modest initial goals are not sufficient for achieving the full benefits of exercise, success with a small goal is a powerful motivator. Rather than giving up, patients feel encouraged and are more likely to set a subsequent, more ambitious goal.

Recommendations. To help patients start exercising, determine how motivated and ready they are. Start by asking them to describe their current activities. Ask if they were ever more active and what they liked about it. Did they experience any benefits? Establish which of increased activity’s benefits—improved sleep, reduced depression, increased energy—would most benefit the patient, based on his or her symptoms.

Discuss barriers to physical activity and encourage problem-solving to overcome them and incorporate physical activity into their lives. Encourage patients to seek support from family, friends, coworkers, and exercise groups.

Help them set realistic, achievable goals. Even a modest 10 minutes of activity has been shown to enhance mood,²⁶ and a 10-minute brisk walk is one-third of the day’s public health guideline. Suggest that patients choose a variety of activities they enjoy.

During follow-up visits, reinforce any progress toward change. When patients’ exercise efforts fall short, explain that the process of becoming more active often includes setbacks. Advise them to seek support and to consider adopting more-achievable goals.

Related resources

• Getting started. Resources on nutrition and physical activity from the National Center for Chronic Disease Prevention and Health Promotion. http://www.cdc.gov/nccdphp/dnpa/physical/starting/index.htm
• Marcus B, Forsyth L. Motivating people to be physically active. Champaign, IL: Human Kinetics, 2002.

Drug brand names

• Fluoxetine • Prozac
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. H, age 26, is being evaluated for moderate to severe depressive symptoms, including oversleeping and overeating. She has had difficulty adhering to medication in the past and is ambivalent about taking antidepressants. She takes a passive approach to managing her depression, preferring to “wait for it to pass.”

Her psychiatrist prescribes fluoxetine, 20 mg in the morning, and recommends that Ms. H change her coping strategies from napping and snacking to increased physical activity. She encourages Ms. H to think about what activities interest her and to set exercise goals.

Ms. H says she has considered buying exercise equipment (an elliptical machine) and increasing her walking outside. She sets a goal to walk 20 minutes most days and to spend 10 to 15 minutes using the elliptical machine while watching television.

Physical activity’s mental health benefits are less well-known than its well-documented medical benefits—reduced risk of heart disease, hypertension, and diabetes; weight control; bone mass preservation; better sleep, and improved cholesterol levels.¹ By encouraging exercise, you can improve patients’ mood, well-being, and quality of life, independent of medication and psychotherapy. In this article, we:

• explore the relationship between physical activity and mental health
• compare exercise with medication and psychotherapies for easing depression
• discuss counseling strategies shown to be effective in helping sedentary patients become more physically active.

Table 1

Why physical activity may improve mental health

Mental benefits of exercise

Adults who exercise regularly report lower levels of depressive and anxiety disorders than the overall U.S. population.² As a therapeutic intervention, exercise has been studied primarily in depressed individuals, although some data also support its efficacy in:

• reducing anxiety symptoms in panic disorder³
• reducing disruptive behavior in developmentally disabled patients⁴
• alleviating chronic fatigue symptoms⁵
• improving body esteem in patients with body image disturbance⁶
• increasing function in chronic pain⁷
• reducing urges to smoke and improving smoking abstinence among nicotine-dependent individuals.⁸

Why exercise helps. Mechanisms that would explain exercise’s positive effect on mood are not well understood.⁹ Physiologic and psychological hypotheses have been suggested (Table 1),^10,11 and researchers are attempting to elucidate them by using animal models.¹³

Case report: Feeling more energetic

At follow-up 6 weeks later, Ms. H. reported a substantial reduction in depressive symptoms. She noted increased energy, improved sleep, decreased overeating, higher self-esteem, and greater confidence in her ability to manage her depression.

Exercising also helped structure her day. She noticed that on days she did not exercise she was more likely to take a nap, miss her medication, or feel pessimistic about her depression.

Exercise as an antidepressant

Exercise vs psychotherapy. Exercise has been shown to be more effective at reducing depressive symptoms than no treatment, occupational therapy, cognitive therapy, health seminars, routine care, or meditation. Interventions used in these meta-analyses ranged from nonaerobic exercise training several times a week to 1 hour of supervised running 4 times a week.¹² Literature reviews also have concluded that exercise training compares favorably with individual or group psychotherapy and with cognitive therapy for treating depression.⁷

Exercise vs medication. Exercise training has also been compared with drug therapy in treating depression.

In a randomized, controlled trial, 156 men and women over age 50 with major depression received exercise training, sertraline, or exercise plus sertraline. Subjects in the exercise groups completed 40 minutes of aerobic exercise (biking or brisk walking/ jogging) 3 times a week. Subjects treated with sertraline received 50 to 200 mg/d, depending on response.

After 16 weeks, all three groups were significantly improved, with no clinically or statistically significant differences in depressive symptoms, as measured with the Hamilton Rating Scale for Depression (HRSD) and Beck Depression Inventory.¹³

In a follow-up study 6 months later,¹⁴ the exercise group had significantly lower rates of relapse (defined as HRSD scores >15 and meeting diagnostic criteria) than did the medication group. Combining exercise with medication did not provide an added benefit in preventing relapse.

Exercise as monotherapy. Some studies have investigated using exercise instead of medication and psychotherapy. Many of these trials, however, were limited by methodologic weaknesses such as nonrandomized samples or lack of appropriate control groups.¹²

To address the need for higher-quality evidence, the Depression Outcomes Study of Exercise (DOSE) is investigating the dose-continued from page 12 response effects of exercise as monotherapy for major depressive disorder (MDD).⁵ The 12-week trial included 80 men and women ages 20 to 45 diagnosed with mild-to-moderate MDD using the Structured Clinical Interview for Depression. They were randomly assigned to one of five supervised exercise regimens:

• 7.0 kcal/kg/week in 3 days/week
• 7.0 kcal/kg/week in 5 days/week
• 17.5 kcal/kg/week in 3 days/week
• 17.5 kcal/kg/week in 5 days/week
• 3 days/week of stretching and flexibility exercises for 15 to 20 min/session.

Table 2

How much physical activity is recommended for adults?

Depressive symptoms were measured with the HRSD and Inventory of Depressive Symptoms (clinician and self-report). Other outcome measures included cardiorespiratory fitness, self-efficacy, and quality of life. Results are being prepared for publication and will likely help clarify the role of physical activity in treating patients with MDD.

Table 3

Why patients don’t exercise: Common barriers they perceive

How much exercise is therapeutic?

In the absence of physical activity guidelines specific to mental health, we suggest using standard public health guidelines (Table 2):

• 30 minutes or more of moderate-intensity physical activity (brisk walking, swimming, dancing, cycling) most days of the week (recommended by the Centers for Disease Control and Prevention and American College of Sports Medicine)¹
• 60 minutes of moderate-intensity physical activity daily for weight loss and maintenance (recommended by the Institute of Medicine).¹⁶

A recent study investigated the effects of exercise duration and intensity on weight loss in overweight, sedentary women. These researchers recommended setting the initial intervention target at 150 minutes or more of moderate-intensity exercise per week and progressing to 60 minutes per day as appropriate.¹⁶

Increasing the number of steps taken per day, as measured by a pedometer, also can be beneficial. Encourage patients to obtain a baseline measure of daily steps and to gradually increase toward a moderate goal of 10,000 steps per day.¹⁷

Case report: Accentuating the positive

On follow-up, Ms. H was quick to report the many barriers to exercise she had experienced and the times she did not meet her goal. Rather than dwell on shortcomings, the psychiatrist redirected her to examine the many positive actions she had taken to manage her depression.

As she considered how to overcome barriers to exercise, she reported increased confidence that she could stick with her medication and exercise regimen. She continues to exercise regularly and adheres to her fluoxetine. Her depressive symptoms remain well-controlled.

Overcoming barriers to exercise

Patient obstacles. Many patients acknowledge that regular exercise makes them feel physically and emotionally healthier but have difficulty exercising long term. Less than one-half of those who start an exercise program stick with it beyond 6 months.¹⁸ Drop-out reasons include injuries, lack of time, and low motivation (Table 3).^19,20

Depressive symptoms—fatigue, loss of interest, low self-esteem, feelings of helplessness, and psychomotor retardation—make exercise adherence even more difficult.

Physician obstacles. The U.S. Preventive Services Task Force recommends that physicians advise all patients to increase physical activity, but the national rate of physician counseling about exercise is low. In a population-based survey of more than 9,000 patients, 34% said their physicians counseled them about exercise at their most recent visit within the past year.²¹

Physician-reported barriers to exercise counseling include:

• competing demands for limited clinical time
• perceived ineffectiveness of advice to exercise
• lack of training and knowledge about exercise counseling and prescription.^22,23

Patients are more likely to become active and continue exercising when their physicians help them set achievable goals.

Project PACE. Physicians can overcome barriers to counseling patients about exercise. Those who participated in Project PACE (Physician-based Assessment and Counseling for Exercise)²⁴ said they felt more confident that they could counsel patients about physical activity in 1 to 5 minutes.

In a controlled study of 212 sedentary adults, patients who received PACE counseling from their physicians significantly increased their minutes of weekly walking compared with a control group. Also, 52% of patients who received PACE counseling adopted some physical activity, compared with 12% of controls.²⁵

Though modest initial goals are not sufficient for achieving the full benefits of exercise, success with a small goal is a powerful motivator. Rather than giving up, patients feel encouraged and are more likely to set a subsequent, more ambitious goal.

Recommendations. To help patients start exercising, determine how motivated and ready they are. Start by asking them to describe their current activities. Ask if they were ever more active and what they liked about it. Did they experience any benefits? Establish which of increased activity’s benefits—improved sleep, reduced depression, increased energy—would most benefit the patient, based on his or her symptoms.

Discuss barriers to physical activity and encourage problem-solving to overcome them and incorporate physical activity into their lives. Encourage patients to seek support from family, friends, coworkers, and exercise groups.

Help them set realistic, achievable goals. Even a modest 10 minutes of activity has been shown to enhance mood,²⁶ and a 10-minute brisk walk is one-third of the day’s public health guideline. Suggest that patients choose a variety of activities they enjoy.

During follow-up visits, reinforce any progress toward change. When patients’ exercise efforts fall short, explain that the process of becoming more active often includes setbacks. Advise them to seek support and to consider adopting more-achievable goals.

Related resources

• Getting started. Resources on nutrition and physical activity from the National Center for Chronic Disease Prevention and Health Promotion. http://www.cdc.gov/nccdphp/dnpa/physical/starting/index.htm
• Marcus B, Forsyth L. Motivating people to be physically active. Champaign, IL: Human Kinetics, 2002.

Drug brand names

• Fluoxetine • Prozac
• Sertraline • Zoloft

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Just three words—“My tummy hurts”—can mobilize a child’s parents into a high state of worry, especially on school days. They wonder: Is our child sick? Should he or she stay home? Why is this happening so often?

Although recurrent abdominal pain (RAP) is real, it usually is not caused by tissue damage or serious physical disease. When children with RAP are referred for psychiatric evaluation—often after extensive medical workups—we can help them and their parents manage the problem and function more normally. This article:

• describes physiologic mechanisms that may underlie recurrent GI distress
• discusses the high correlation of psychiatric comorbidities with RAP
• recommends judicious laboratory testing
• reviews evidence on medications and psychotherapies to improve RAP symptoms
• offers advice on building a therapeutic alliance with the patient and family.

Figure Comorbid anxiety and depressive disorders in children with RAP

Children with functional RAP are much more likely to be anxious or depressed than similar pain-free children. A recent blinded study followed 80 children ages 8 to 15 (42 with RAP and 38 controls) identified through screening at primary care pediatric offices. Each was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime version (K-SADS-PL). Percentage meeting diagnostic criteria

Source: Reference 5.

RAP: A ‘Functional’ disorder

RAP is a somatoform (or “functional”) disorder, defined as physical symptoms not fully explained by a medical condition, effects of a substance, or another mental disorder. Symptoms cause distress and/or functional impairment and are not intentionally produced.¹

A patient with RAP experiences at least three episodes of abdominal pain over 3 months that interfere with daily activities.² RAP affects 7% to 25% of school-aged children and adolescents,³ most of whom have a functional disorder.⁴

RAP is equally common among prepubertal boys and girls but more common among girls during adolescence.³ RAP can impair school attendance and performance and stigmatize a child as “sickly.”

Common comorbid symptoms

Physical. Besides stomach pain, children with RAP often experience headaches (including migraines), other GI symptoms, general aches and pains, dizziness, and fatigue.

Patients with RAP who do not experience GI bleeding, anemia, fever, weight loss, growth failure, or persistent vomiting most likely do not have a serious underlying disease.

Psychiatric. Children with RAP have much higher rates of anxiety (80%) and depressive (40%) disorders than do their unaffected peers (Figure).⁵ We have also seen higher levels of suicidal thinking in children with RAP in primary care settings compared with pain-free controls (14% vs. 4%, P = 0.04; unpublished data).

In most cases, psychiatric comorbidities appear to precede or coincide with RAP onset. Separation fears, generalized anxiety, and social anxiety in particular are common in patients with RAP yet are seldom recognized in medical settings.

Having childhood RAP increases the risk of anxiety, depression, and hypochondriacal fears in adulthood.⁶ We do not know whether early intervention prevents later disability.

Use of medical services. Abdominal pain accounts for 2% to 4% of all pediatric office visits.⁷ In one study, 8% of middle school and high school students said they had visited a physician for evaluation of stomach pain during the previous year.⁸ Children with RAP make more ambulatory health and mental health visits than peers⁹ and are at risk for unnecessary and potentially dangerous medical tests, procedures, and treatments, including abdominal surgery.¹⁰

Four functional GI disorders

To better characterize youths with functional RAP, symptom-based criteria have been developed and applied for functional GI disorders, defined as chronic or recurrent GI symptoms without explanatory structural or biochemical abnormalities.¹¹ Four such disorders are relevant in children with RAP.

Irritable bowel syndrome (IBS): RAP with at least two of the following symptoms: relief with defecation, change in stool frequency, and change in stool form or appearance (occurs in approximately 50% of RAP cases).

Functional dyspepsia: RAP centered in the upper abdomen that is not associated with changes in bowel habits.

Abdominal migraine: Paroxysmal midline abdominal pain lasting 2 hours to several days with symptom-free intervals of weeks to months and at least two of the following: headache during episodes, photophobia during episodes, unilateral headache, aura, and a family history of migraine.

Functional abdominal pain: Continuous or nearly continuous abdominal pain for 6 months or more.

The reliability, validity, and clinical relevance of these criteria have not been demonstrated. Some children with RAP do not meet any criteria for a specific functional GI disorder.

Gut-brain connections. RAP may be associated with a heightened sensitivity to visceral sensations (visceral hyperalgesia) and a low pressure-pain threshold, leading to speculation that these children are hypersensitive to pain.

High rates of anxiety disorders and temperamental harm avoidance also are seen in patients with RAP, along with a tendency to develop pain when faced with unexpected events. Whether these children are more likely than others to perceive novel internal or external perceptions as threatening is open to debate.

Table 1

Recurrent abdominal pain: 8 steps to assessment and diagnosis

Serotonin communicates nociceptive information between the gut and brain and may mediate visceral hyperalgesia. Gut enterochromaffin cells contain more than 90% of the body’s total serotonin. They act as sensory transducers, releasing serotonin in response to increased intraluminal pressure or inflammation.

The released serotonin can cause abdominal discomfort by stimulating 5-HT 3 receptors on vagal afferents and can influence gut peristaltic activity by stimulating enteric afferents. The same serotonin transporter responsible for CNS serotonin reuptake is expressed throughout the gut.

A constellation of clues

The ideal RAP evaluation includes information from the child, parents, educators, and other health care professionals (Table 1).

Begin by acknowledging the patient’s suffering and the parent’s concerns; do not challenge the pain’s subjective reality. Rather than prejudging its cause, document the pain’s timing, context, and characteristics, and review the patient’s history. A constellation of clues is most suggestive of RAP (Table 2); single clues are not definitive.^12,13

Table 2

Clues that suggest functional pain*

Diagnostic testing. Be judicious in selecting diagnostic tests and procedures. Continuing to order studies in a haphazard effort to rule out disease can generate concerns that “the doctor doesn’t know what’s wrong” and heighten the family’s fear that a disease has been missed.

The process of “ruling out” physical disease may have no apparent end. Unless you are reasonably comfortable that a serious physical disease has not been missed, it is difficult to explain RAP to the patient and family and lay the foundation for intervention.

On the other hand, you must balance the importance of minimizing your own and the family’s anxiety about unrecognized disease against the physical and psychological risks and costs associated with medical tests and procedures.

Social assessment. Assess social and familial reinforcement (secondary gain) of the pain. Parents sometimes inadvertently encourage their children’s sick-role behaviors by providing excessive attention, rewards, or opportunities to avoid uncomfortable situations. RAP can become an excuse for poor performance (self-handicapping), particularly in children with a learning disorder.

How to deliver the diagnosis

Functional abdominal pain is essentially a clinical diagnosis that relies on presentation, course, and findings. As mentioned, a constellation of “clues” is most supportive, as is having typical IBS symptoms.

Before declaring the diagnosis, discuss with the family the patient’s physical, emotional, and behavioral symptoms and the context in which RAP developed. Doing so can help maintain your credibility and establish a consensus.

Once you declare the diagnosis, discuss it clearly and frankly. Families are not likely to be reassured if you do not offer a plausible explanation for the lack of physical findings.

Precautions. When a definitive diagnosis is not possible, acknowledge that uncertainty. Although you must discuss any recognized psychiatric comorbidity, attempting to “explain” that the disorder is causing the pain is usually impractical and intellectually dishonest.

Also, given the pervasive nature of stigma, do not convey embarrassment or unease about diagnosing functional RAP or any comorbid psychiatric disorder.

Follow-up testing. Once you diagnose functional RAP, further testing is generally not necessary. Tests might be indicated if you:

• receive new information
• observe a change in clinical status
• or are convinced that treatment will not work unless the family is reassured by further investigation.

Collaborative treatment

Reassurance and education. Reassurance that the patient does not have a serious physical disease is necessary but rarely sufficient. Explain that the child’s pain does not appear to reflect tissue damage and is not threatening. On the other hand, avoid giving excessive reassurance, particularly when obsessional illness worry and hypochondriacal fears are prominent. Address illness worry as a problem to be solved together.

Discuss with the patient and family what is known and not known about functional RAP, and encourage them to ask questions. This is an opportunity for you to instill hope and cultivate positive expectations, but avoid promising cure. Discuss the gut-brain connection and relevance of visceral hyperalgesia, including serotonin’s potential roles in RAP pathogenesis.

Partners in care. Collaborative treatment increases the likelihood of success. Discuss the importance of a therapeutic partnership, and clarify any areas of disagreement with the diagnosis or treatment plan.

Clearly delineate your roles and responsibilities and those of the patient, family, and other health care team members. Poor communication is pediatricians’ most common complaint about psychiatrists.¹⁴ Good interdisciplinary communication decreases the chance that treatment strategies will be duplicated, diluted, or misinterpreted.

Consolidate medical care with a single clinician—often the primary care physician—based on discussions with the patient, family, and health care team. The coordinating clinician can mediate between the school and family when tensions develop over poor attendance or requests for special treatment. It is often useful for this clinician to spell out:

• what constitutes a legitimate medical excuse for school absence
• who will legitimize excuses.

All parties should understand that the school will view an unexcused absence as truancy and act appropriately.

Diet and lifestyle. Encourage the patient to maintain a regular schedule and a healthy diet. Specific dietary interventions have not been proven effective, despite speculation that lack of dietary fiber or lactose intolerance might cause RAP.^15,16 Also encourage adequate sleep and regular exercise.

Medication and psychotherapy

Because no strong evidence-based guidelines address pediatric RAP intervention, family preferences usually guide initial treatment decisions. This highlights the importance of good communication and a therapeutic partnership among the clinician, family, and patient.

Antispasmodics, acid reducers, and antidepressants are commonly prescribed for RAP, though none are well-supported in the literature and no controlled studies have gauged medication’s impact on psychiatric comorbidity.¹⁶

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) might help relieve RAP symptoms, but the evidence is inconclusive. SSRIs are considered potentially beneficial in RAP because they may help communicate nociceptive information between the gut and brain and mediate visceral hyperalgesia.

SSRIs at first may increase serotonin at the synapse, which one might assume would to worsen abdominal symptoms. However, ongoing SSRI use could “down-regulate” postsynaptic 5-HT₃ receptors and desensitize postsynaptic cells to the effects of local serotonin.

Our group recently conducted a 12-week open trial of citalopram for functional pediatric RAP.¹⁷ The 25 participants received 10 mg/d the first week, then 20 mg/d thereafter if tolerated. At week 4, nonresponders and partial responders who were tolerating the medication began receiving 40 mg/d.

Table 3

SSRI daily dosing for pediatric RAP

At trial’s end, more than two-thirds of participants were taking 40 mg/d. We rated 21 of 25 patients (84%) as “much improved” or “very much improved,” using the Clinical Global Impression-Improvement scale. Abdominal pain, anxiety, depression, other somatic symptoms, and functional impairment all improved significantly during treatment. Suicidal thoughts diminished progressively from baseline, and no patient reported suicidal thinking at study’s end. Citalopram was generally well tolerated.

With SSRI treatment, start at a low dosage for 3 to 7 days (Table 3). If tolerated, increase to a typical therapeutic dosage. If symptoms fail to respond after 2 or 3 weeks, consider a higher dosage. A short course of an oral benzodiazepine (such as clonazepam, 0.25 mg bid) during the first weeks of SSRI treatment sometimes helps particularly anxious patients or those whose pain appears closely associated with anxiety or “stress.”

Pediatric gastroenterologists often prescribe a low-dose tricyclic antidepressant as first-line therapy, but we discourage this. TCAs lack efficacy in pediatric depression and pose a greater risk of side effects and safety concerns than SSRIs.¹⁸

Other agents have been tried for RAP-associated conditions:

Famotidine, a histamine type 2 receptor blocker, may reduce pain in children with dyspepsia and RAP.¹⁹

Peppermint oil reduced abdominal pain in one study of children with IBS but had little effect on other symptoms.²⁰

Medications such as alosetron and tegaserod that interrupt serotonergic neurotransmission in the gut have shown benefit in adults with IBS but have not been studied in children.

Psychotherapy. A few small studies suggest that cognitive-behavioral therapies (CBT) are helpful in RAP, but CBT may be difficult to deliver in medical settings.^21,22 A simplified “rehabilitative” approach that incorporates CBT principles involves having the clinician and patient view RAP as a challenge to be overcome, rather than a burden to be endured. Such an approach emphasizes the child’s fundamental strength and adaptability rather than vulnerabilities.

The goal of therapy is redirected from finding a cure to coping with and overcoming the problem. This approach challenges the notion that the child cannot resume normal function until the pain is completely gone. It encourages active, problem-focused coping, and discourages passive acceptance—which is associated with greater symptom burden and functional impairment.

Work with parents to reinforce the child’s health-promoting behaviors and minimize negative and social reinforcements (secondary gain) associated with RAP. Advise parents to:

• encourage and reward full school attendance
• avoid home-bound instruction
• expect the child to function despite physical distress
• insist that the child perform age-appropriate household chores and other responsibilities.

Self-management skills—such as relaxation training, hypnosis, biofeedback, and guided imagery—may help reduce pain and manage physiologic arousal.¹⁶ Deception strategies such as placebo or sham interventions are unethical and impractical.

Related resources

• Campo JV. Functional recurrent abdominal pain in children and adolescents. Digestive Health Matters 2003;12(3):15-7.
• International Foundation for Functional Gastrointestinal Disorders. www.iffgd.org
• University of Pittsburgh. Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders. www.moodykids.org

Drug brand names

• Alosetron • Lotronex
• Citalopram • Celexa
• Clonazepam • Klonopin
• Escitalopram • Lexapro
• Famotidine • Pepcid
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Sertraline • Zoloft
• Tegaserod • Zelnorm

Disclosure

Dr. Campo’s work has been supported by the National Institute of Mental Health (grant MH01780) and in part by the Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders (grant MH66371). He also receives grants from Forest Pharmaceuticals and is a consultant to Eli Lilly and Co.

Just three words—“My tummy hurts”—can mobilize a child’s parents into a high state of worry, especially on school days. They wonder: Is our child sick? Should he or she stay home? Why is this happening so often?

Although recurrent abdominal pain (RAP) is real, it usually is not caused by tissue damage or serious physical disease. When children with RAP are referred for psychiatric evaluation—often after extensive medical workups—we can help them and their parents manage the problem and function more normally. This article:

• describes physiologic mechanisms that may underlie recurrent GI distress
• discusses the high correlation of psychiatric comorbidities with RAP
• recommends judicious laboratory testing
• reviews evidence on medications and psychotherapies to improve RAP symptoms
• offers advice on building a therapeutic alliance with the patient and family.

Figure Comorbid anxiety and depressive disorders in children with RAP

Children with functional RAP are much more likely to be anxious or depressed than similar pain-free children. A recent blinded study followed 80 children ages 8 to 15 (42 with RAP and 38 controls) identified through screening at primary care pediatric offices. Each was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime version (K-SADS-PL). Percentage meeting diagnostic criteria

Source: Reference 5.

RAP: A ‘Functional’ disorder

RAP is a somatoform (or “functional”) disorder, defined as physical symptoms not fully explained by a medical condition, effects of a substance, or another mental disorder. Symptoms cause distress and/or functional impairment and are not intentionally produced.¹

A patient with RAP experiences at least three episodes of abdominal pain over 3 months that interfere with daily activities.² RAP affects 7% to 25% of school-aged children and adolescents,³ most of whom have a functional disorder.⁴

RAP is equally common among prepubertal boys and girls but more common among girls during adolescence.³ RAP can impair school attendance and performance and stigmatize a child as “sickly.”

Common comorbid symptoms

Physical. Besides stomach pain, children with RAP often experience headaches (including migraines), other GI symptoms, general aches and pains, dizziness, and fatigue.

Patients with RAP who do not experience GI bleeding, anemia, fever, weight loss, growth failure, or persistent vomiting most likely do not have a serious underlying disease.

Psychiatric. Children with RAP have much higher rates of anxiety (80%) and depressive (40%) disorders than do their unaffected peers (Figure).⁵ We have also seen higher levels of suicidal thinking in children with RAP in primary care settings compared with pain-free controls (14% vs. 4%, P = 0.04; unpublished data).

In most cases, psychiatric comorbidities appear to precede or coincide with RAP onset. Separation fears, generalized anxiety, and social anxiety in particular are common in patients with RAP yet are seldom recognized in medical settings.

Having childhood RAP increases the risk of anxiety, depression, and hypochondriacal fears in adulthood.⁶ We do not know whether early intervention prevents later disability.

Use of medical services. Abdominal pain accounts for 2% to 4% of all pediatric office visits.⁷ In one study, 8% of middle school and high school students said they had visited a physician for evaluation of stomach pain during the previous year.⁸ Children with RAP make more ambulatory health and mental health visits than peers⁹ and are at risk for unnecessary and potentially dangerous medical tests, procedures, and treatments, including abdominal surgery.¹⁰

Four functional GI disorders

To better characterize youths with functional RAP, symptom-based criteria have been developed and applied for functional GI disorders, defined as chronic or recurrent GI symptoms without explanatory structural or biochemical abnormalities.¹¹ Four such disorders are relevant in children with RAP.

Irritable bowel syndrome (IBS): RAP with at least two of the following symptoms: relief with defecation, change in stool frequency, and change in stool form or appearance (occurs in approximately 50% of RAP cases).

Functional dyspepsia: RAP centered in the upper abdomen that is not associated with changes in bowel habits.

Abdominal migraine: Paroxysmal midline abdominal pain lasting 2 hours to several days with symptom-free intervals of weeks to months and at least two of the following: headache during episodes, photophobia during episodes, unilateral headache, aura, and a family history of migraine.

Functional abdominal pain: Continuous or nearly continuous abdominal pain for 6 months or more.

The reliability, validity, and clinical relevance of these criteria have not been demonstrated. Some children with RAP do not meet any criteria for a specific functional GI disorder.

Gut-brain connections. RAP may be associated with a heightened sensitivity to visceral sensations (visceral hyperalgesia) and a low pressure-pain threshold, leading to speculation that these children are hypersensitive to pain.

High rates of anxiety disorders and temperamental harm avoidance also are seen in patients with RAP, along with a tendency to develop pain when faced with unexpected events. Whether these children are more likely than others to perceive novel internal or external perceptions as threatening is open to debate.

Table 1

Recurrent abdominal pain: 8 steps to assessment and diagnosis

Serotonin communicates nociceptive information between the gut and brain and may mediate visceral hyperalgesia. Gut enterochromaffin cells contain more than 90% of the body’s total serotonin. They act as sensory transducers, releasing serotonin in response to increased intraluminal pressure or inflammation.

The released serotonin can cause abdominal discomfort by stimulating 5-HT 3 receptors on vagal afferents and can influence gut peristaltic activity by stimulating enteric afferents. The same serotonin transporter responsible for CNS serotonin reuptake is expressed throughout the gut.

A constellation of clues

The ideal RAP evaluation includes information from the child, parents, educators, and other health care professionals (Table 1).

Begin by acknowledging the patient’s suffering and the parent’s concerns; do not challenge the pain’s subjective reality. Rather than prejudging its cause, document the pain’s timing, context, and characteristics, and review the patient’s history. A constellation of clues is most suggestive of RAP (Table 2); single clues are not definitive.^12,13

Table 2

Clues that suggest functional pain*

Diagnostic testing. Be judicious in selecting diagnostic tests and procedures. Continuing to order studies in a haphazard effort to rule out disease can generate concerns that “the doctor doesn’t know what’s wrong” and heighten the family’s fear that a disease has been missed.

The process of “ruling out” physical disease may have no apparent end. Unless you are reasonably comfortable that a serious physical disease has not been missed, it is difficult to explain RAP to the patient and family and lay the foundation for intervention.

On the other hand, you must balance the importance of minimizing your own and the family’s anxiety about unrecognized disease against the physical and psychological risks and costs associated with medical tests and procedures.

Social assessment. Assess social and familial reinforcement (secondary gain) of the pain. Parents sometimes inadvertently encourage their children’s sick-role behaviors by providing excessive attention, rewards, or opportunities to avoid uncomfortable situations. RAP can become an excuse for poor performance (self-handicapping), particularly in children with a learning disorder.

How to deliver the diagnosis

Functional abdominal pain is essentially a clinical diagnosis that relies on presentation, course, and findings. As mentioned, a constellation of “clues” is most supportive, as is having typical IBS symptoms.

Before declaring the diagnosis, discuss with the family the patient’s physical, emotional, and behavioral symptoms and the context in which RAP developed. Doing so can help maintain your credibility and establish a consensus.

Once you declare the diagnosis, discuss it clearly and frankly. Families are not likely to be reassured if you do not offer a plausible explanation for the lack of physical findings.

Precautions. When a definitive diagnosis is not possible, acknowledge that uncertainty. Although you must discuss any recognized psychiatric comorbidity, attempting to “explain” that the disorder is causing the pain is usually impractical and intellectually dishonest.

Also, given the pervasive nature of stigma, do not convey embarrassment or unease about diagnosing functional RAP or any comorbid psychiatric disorder.

Follow-up testing. Once you diagnose functional RAP, further testing is generally not necessary. Tests might be indicated if you:

• receive new information
• observe a change in clinical status
• or are convinced that treatment will not work unless the family is reassured by further investigation.

Collaborative treatment

Reassurance and education. Reassurance that the patient does not have a serious physical disease is necessary but rarely sufficient. Explain that the child’s pain does not appear to reflect tissue damage and is not threatening. On the other hand, avoid giving excessive reassurance, particularly when obsessional illness worry and hypochondriacal fears are prominent. Address illness worry as a problem to be solved together.

Discuss with the patient and family what is known and not known about functional RAP, and encourage them to ask questions. This is an opportunity for you to instill hope and cultivate positive expectations, but avoid promising cure. Discuss the gut-brain connection and relevance of visceral hyperalgesia, including serotonin’s potential roles in RAP pathogenesis.

Partners in care. Collaborative treatment increases the likelihood of success. Discuss the importance of a therapeutic partnership, and clarify any areas of disagreement with the diagnosis or treatment plan.

Clearly delineate your roles and responsibilities and those of the patient, family, and other health care team members. Poor communication is pediatricians’ most common complaint about psychiatrists.¹⁴ Good interdisciplinary communication decreases the chance that treatment strategies will be duplicated, diluted, or misinterpreted.

Consolidate medical care with a single clinician—often the primary care physician—based on discussions with the patient, family, and health care team. The coordinating clinician can mediate between the school and family when tensions develop over poor attendance or requests for special treatment. It is often useful for this clinician to spell out:

• what constitutes a legitimate medical excuse for school absence
• who will legitimize excuses.

All parties should understand that the school will view an unexcused absence as truancy and act appropriately.

Diet and lifestyle. Encourage the patient to maintain a regular schedule and a healthy diet. Specific dietary interventions have not been proven effective, despite speculation that lack of dietary fiber or lactose intolerance might cause RAP.^15,16 Also encourage adequate sleep and regular exercise.

Medication and psychotherapy

Because no strong evidence-based guidelines address pediatric RAP intervention, family preferences usually guide initial treatment decisions. This highlights the importance of good communication and a therapeutic partnership among the clinician, family, and patient.

Antispasmodics, acid reducers, and antidepressants are commonly prescribed for RAP, though none are well-supported in the literature and no controlled studies have gauged medication’s impact on psychiatric comorbidity.¹⁶

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) might help relieve RAP symptoms, but the evidence is inconclusive. SSRIs are considered potentially beneficial in RAP because they may help communicate nociceptive information between the gut and brain and mediate visceral hyperalgesia.

SSRIs at first may increase serotonin at the synapse, which one might assume would to worsen abdominal symptoms. However, ongoing SSRI use could “down-regulate” postsynaptic 5-HT₃ receptors and desensitize postsynaptic cells to the effects of local serotonin.

Our group recently conducted a 12-week open trial of citalopram for functional pediatric RAP.¹⁷ The 25 participants received 10 mg/d the first week, then 20 mg/d thereafter if tolerated. At week 4, nonresponders and partial responders who were tolerating the medication began receiving 40 mg/d.

Table 3

SSRI daily dosing for pediatric RAP

At trial’s end, more than two-thirds of participants were taking 40 mg/d. We rated 21 of 25 patients (84%) as “much improved” or “very much improved,” using the Clinical Global Impression-Improvement scale. Abdominal pain, anxiety, depression, other somatic symptoms, and functional impairment all improved significantly during treatment. Suicidal thoughts diminished progressively from baseline, and no patient reported suicidal thinking at study’s end. Citalopram was generally well tolerated.

With SSRI treatment, start at a low dosage for 3 to 7 days (Table 3). If tolerated, increase to a typical therapeutic dosage. If symptoms fail to respond after 2 or 3 weeks, consider a higher dosage. A short course of an oral benzodiazepine (such as clonazepam, 0.25 mg bid) during the first weeks of SSRI treatment sometimes helps particularly anxious patients or those whose pain appears closely associated with anxiety or “stress.”

Pediatric gastroenterologists often prescribe a low-dose tricyclic antidepressant as first-line therapy, but we discourage this. TCAs lack efficacy in pediatric depression and pose a greater risk of side effects and safety concerns than SSRIs.¹⁸

Other agents have been tried for RAP-associated conditions:

Famotidine, a histamine type 2 receptor blocker, may reduce pain in children with dyspepsia and RAP.¹⁹

Peppermint oil reduced abdominal pain in one study of children with IBS but had little effect on other symptoms.²⁰

Medications such as alosetron and tegaserod that interrupt serotonergic neurotransmission in the gut have shown benefit in adults with IBS but have not been studied in children.

Psychotherapy. A few small studies suggest that cognitive-behavioral therapies (CBT) are helpful in RAP, but CBT may be difficult to deliver in medical settings.^21,22 A simplified “rehabilitative” approach that incorporates CBT principles involves having the clinician and patient view RAP as a challenge to be overcome, rather than a burden to be endured. Such an approach emphasizes the child’s fundamental strength and adaptability rather than vulnerabilities.

The goal of therapy is redirected from finding a cure to coping with and overcoming the problem. This approach challenges the notion that the child cannot resume normal function until the pain is completely gone. It encourages active, problem-focused coping, and discourages passive acceptance—which is associated with greater symptom burden and functional impairment.

Work with parents to reinforce the child’s health-promoting behaviors and minimize negative and social reinforcements (secondary gain) associated with RAP. Advise parents to:

• encourage and reward full school attendance
• avoid home-bound instruction
• expect the child to function despite physical distress
• insist that the child perform age-appropriate household chores and other responsibilities.

Self-management skills—such as relaxation training, hypnosis, biofeedback, and guided imagery—may help reduce pain and manage physiologic arousal.¹⁶ Deception strategies such as placebo or sham interventions are unethical and impractical.

Related resources

• Campo JV. Functional recurrent abdominal pain in children and adolescents. Digestive Health Matters 2003;12(3):15-7.
• International Foundation for Functional Gastrointestinal Disorders. www.iffgd.org
• University of Pittsburgh. Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders. www.moodykids.org

Drug brand names

• Alosetron • Lotronex
• Citalopram • Celexa
• Clonazepam • Klonopin
• Escitalopram • Lexapro
• Famotidine • Pepcid
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Sertraline • Zoloft
• Tegaserod • Zelnorm

Disclosure

Dr. Campo’s work has been supported by the National Institute of Mental Health (grant MH01780) and in part by the Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders (grant MH66371). He also receives grants from Forest Pharmaceuticals and is a consultant to Eli Lilly and Co.

Just three words—“My tummy hurts”—can mobilize a child’s parents into a high state of worry, especially on school days. They wonder: Is our child sick? Should he or she stay home? Why is this happening so often?

Although recurrent abdominal pain (RAP) is real, it usually is not caused by tissue damage or serious physical disease. When children with RAP are referred for psychiatric evaluation—often after extensive medical workups—we can help them and their parents manage the problem and function more normally. This article:

• describes physiologic mechanisms that may underlie recurrent GI distress
• discusses the high correlation of psychiatric comorbidities with RAP
• recommends judicious laboratory testing
• reviews evidence on medications and psychotherapies to improve RAP symptoms
• offers advice on building a therapeutic alliance with the patient and family.

Figure Comorbid anxiety and depressive disorders in children with RAP

Children with functional RAP are much more likely to be anxious or depressed than similar pain-free children. A recent blinded study followed 80 children ages 8 to 15 (42 with RAP and 38 controls) identified through screening at primary care pediatric offices. Each was assessed using the Schedule for Affective Disorders and Schizophrenia for School Age Children, Present and Lifetime version (K-SADS-PL). Percentage meeting diagnostic criteria

Source: Reference 5.

RAP: A ‘Functional’ disorder

RAP is a somatoform (or “functional”) disorder, defined as physical symptoms not fully explained by a medical condition, effects of a substance, or another mental disorder. Symptoms cause distress and/or functional impairment and are not intentionally produced.¹

A patient with RAP experiences at least three episodes of abdominal pain over 3 months that interfere with daily activities.² RAP affects 7% to 25% of school-aged children and adolescents,³ most of whom have a functional disorder.⁴

RAP is equally common among prepubertal boys and girls but more common among girls during adolescence.³ RAP can impair school attendance and performance and stigmatize a child as “sickly.”

Common comorbid symptoms

Physical. Besides stomach pain, children with RAP often experience headaches (including migraines), other GI symptoms, general aches and pains, dizziness, and fatigue.

Patients with RAP who do not experience GI bleeding, anemia, fever, weight loss, growth failure, or persistent vomiting most likely do not have a serious underlying disease.

Psychiatric. Children with RAP have much higher rates of anxiety (80%) and depressive (40%) disorders than do their unaffected peers (Figure).⁵ We have also seen higher levels of suicidal thinking in children with RAP in primary care settings compared with pain-free controls (14% vs. 4%, P = 0.04; unpublished data).

In most cases, psychiatric comorbidities appear to precede or coincide with RAP onset. Separation fears, generalized anxiety, and social anxiety in particular are common in patients with RAP yet are seldom recognized in medical settings.

Having childhood RAP increases the risk of anxiety, depression, and hypochondriacal fears in adulthood.⁶ We do not know whether early intervention prevents later disability.

Use of medical services. Abdominal pain accounts for 2% to 4% of all pediatric office visits.⁷ In one study, 8% of middle school and high school students said they had visited a physician for evaluation of stomach pain during the previous year.⁸ Children with RAP make more ambulatory health and mental health visits than peers⁹ and are at risk for unnecessary and potentially dangerous medical tests, procedures, and treatments, including abdominal surgery.¹⁰

Four functional GI disorders

To better characterize youths with functional RAP, symptom-based criteria have been developed and applied for functional GI disorders, defined as chronic or recurrent GI symptoms without explanatory structural or biochemical abnormalities.¹¹ Four such disorders are relevant in children with RAP.

Irritable bowel syndrome (IBS): RAP with at least two of the following symptoms: relief with defecation, change in stool frequency, and change in stool form or appearance (occurs in approximately 50% of RAP cases).

Functional dyspepsia: RAP centered in the upper abdomen that is not associated with changes in bowel habits.

Abdominal migraine: Paroxysmal midline abdominal pain lasting 2 hours to several days with symptom-free intervals of weeks to months and at least two of the following: headache during episodes, photophobia during episodes, unilateral headache, aura, and a family history of migraine.

Functional abdominal pain: Continuous or nearly continuous abdominal pain for 6 months or more.

The reliability, validity, and clinical relevance of these criteria have not been demonstrated. Some children with RAP do not meet any criteria for a specific functional GI disorder.

Gut-brain connections. RAP may be associated with a heightened sensitivity to visceral sensations (visceral hyperalgesia) and a low pressure-pain threshold, leading to speculation that these children are hypersensitive to pain.

High rates of anxiety disorders and temperamental harm avoidance also are seen in patients with RAP, along with a tendency to develop pain when faced with unexpected events. Whether these children are more likely than others to perceive novel internal or external perceptions as threatening is open to debate.

Table 1

Recurrent abdominal pain: 8 steps to assessment and diagnosis

Serotonin communicates nociceptive information between the gut and brain and may mediate visceral hyperalgesia. Gut enterochromaffin cells contain more than 90% of the body’s total serotonin. They act as sensory transducers, releasing serotonin in response to increased intraluminal pressure or inflammation.

The released serotonin can cause abdominal discomfort by stimulating 5-HT 3 receptors on vagal afferents and can influence gut peristaltic activity by stimulating enteric afferents. The same serotonin transporter responsible for CNS serotonin reuptake is expressed throughout the gut.

A constellation of clues

The ideal RAP evaluation includes information from the child, parents, educators, and other health care professionals (Table 1).

Begin by acknowledging the patient’s suffering and the parent’s concerns; do not challenge the pain’s subjective reality. Rather than prejudging its cause, document the pain’s timing, context, and characteristics, and review the patient’s history. A constellation of clues is most suggestive of RAP (Table 2); single clues are not definitive.^12,13

Table 2

Clues that suggest functional pain*

Diagnostic testing. Be judicious in selecting diagnostic tests and procedures. Continuing to order studies in a haphazard effort to rule out disease can generate concerns that “the doctor doesn’t know what’s wrong” and heighten the family’s fear that a disease has been missed.

The process of “ruling out” physical disease may have no apparent end. Unless you are reasonably comfortable that a serious physical disease has not been missed, it is difficult to explain RAP to the patient and family and lay the foundation for intervention.

On the other hand, you must balance the importance of minimizing your own and the family’s anxiety about unrecognized disease against the physical and psychological risks and costs associated with medical tests and procedures.

Social assessment. Assess social and familial reinforcement (secondary gain) of the pain. Parents sometimes inadvertently encourage their children’s sick-role behaviors by providing excessive attention, rewards, or opportunities to avoid uncomfortable situations. RAP can become an excuse for poor performance (self-handicapping), particularly in children with a learning disorder.

How to deliver the diagnosis

Functional abdominal pain is essentially a clinical diagnosis that relies on presentation, course, and findings. As mentioned, a constellation of “clues” is most supportive, as is having typical IBS symptoms.

Before declaring the diagnosis, discuss with the family the patient’s physical, emotional, and behavioral symptoms and the context in which RAP developed. Doing so can help maintain your credibility and establish a consensus.

Once you declare the diagnosis, discuss it clearly and frankly. Families are not likely to be reassured if you do not offer a plausible explanation for the lack of physical findings.

Precautions. When a definitive diagnosis is not possible, acknowledge that uncertainty. Although you must discuss any recognized psychiatric comorbidity, attempting to “explain” that the disorder is causing the pain is usually impractical and intellectually dishonest.

Also, given the pervasive nature of stigma, do not convey embarrassment or unease about diagnosing functional RAP or any comorbid psychiatric disorder.

Follow-up testing. Once you diagnose functional RAP, further testing is generally not necessary. Tests might be indicated if you:

• receive new information
• observe a change in clinical status
• or are convinced that treatment will not work unless the family is reassured by further investigation.

Collaborative treatment

Reassurance and education. Reassurance that the patient does not have a serious physical disease is necessary but rarely sufficient. Explain that the child’s pain does not appear to reflect tissue damage and is not threatening. On the other hand, avoid giving excessive reassurance, particularly when obsessional illness worry and hypochondriacal fears are prominent. Address illness worry as a problem to be solved together.

Discuss with the patient and family what is known and not known about functional RAP, and encourage them to ask questions. This is an opportunity for you to instill hope and cultivate positive expectations, but avoid promising cure. Discuss the gut-brain connection and relevance of visceral hyperalgesia, including serotonin’s potential roles in RAP pathogenesis.

Partners in care. Collaborative treatment increases the likelihood of success. Discuss the importance of a therapeutic partnership, and clarify any areas of disagreement with the diagnosis or treatment plan.

Clearly delineate your roles and responsibilities and those of the patient, family, and other health care team members. Poor communication is pediatricians’ most common complaint about psychiatrists.¹⁴ Good interdisciplinary communication decreases the chance that treatment strategies will be duplicated, diluted, or misinterpreted.

Consolidate medical care with a single clinician—often the primary care physician—based on discussions with the patient, family, and health care team. The coordinating clinician can mediate between the school and family when tensions develop over poor attendance or requests for special treatment. It is often useful for this clinician to spell out:

• what constitutes a legitimate medical excuse for school absence
• who will legitimize excuses.

All parties should understand that the school will view an unexcused absence as truancy and act appropriately.

Diet and lifestyle. Encourage the patient to maintain a regular schedule and a healthy diet. Specific dietary interventions have not been proven effective, despite speculation that lack of dietary fiber or lactose intolerance might cause RAP.^15,16 Also encourage adequate sleep and regular exercise.

Medication and psychotherapy

Because no strong evidence-based guidelines address pediatric RAP intervention, family preferences usually guide initial treatment decisions. This highlights the importance of good communication and a therapeutic partnership among the clinician, family, and patient.

Antispasmodics, acid reducers, and antidepressants are commonly prescribed for RAP, though none are well-supported in the literature and no controlled studies have gauged medication’s impact on psychiatric comorbidity.¹⁶

Antidepressants. Selective serotonin reuptake inhibitors (SSRIs) might help relieve RAP symptoms, but the evidence is inconclusive. SSRIs are considered potentially beneficial in RAP because they may help communicate nociceptive information between the gut and brain and mediate visceral hyperalgesia.

SSRIs at first may increase serotonin at the synapse, which one might assume would to worsen abdominal symptoms. However, ongoing SSRI use could “down-regulate” postsynaptic 5-HT₃ receptors and desensitize postsynaptic cells to the effects of local serotonin.

Our group recently conducted a 12-week open trial of citalopram for functional pediatric RAP.¹⁷ The 25 participants received 10 mg/d the first week, then 20 mg/d thereafter if tolerated. At week 4, nonresponders and partial responders who were tolerating the medication began receiving 40 mg/d.

Table 3

SSRI daily dosing for pediatric RAP

At trial’s end, more than two-thirds of participants were taking 40 mg/d. We rated 21 of 25 patients (84%) as “much improved” or “very much improved,” using the Clinical Global Impression-Improvement scale. Abdominal pain, anxiety, depression, other somatic symptoms, and functional impairment all improved significantly during treatment. Suicidal thoughts diminished progressively from baseline, and no patient reported suicidal thinking at study’s end. Citalopram was generally well tolerated.

With SSRI treatment, start at a low dosage for 3 to 7 days (Table 3). If tolerated, increase to a typical therapeutic dosage. If symptoms fail to respond after 2 or 3 weeks, consider a higher dosage. A short course of an oral benzodiazepine (such as clonazepam, 0.25 mg bid) during the first weeks of SSRI treatment sometimes helps particularly anxious patients or those whose pain appears closely associated with anxiety or “stress.”

Pediatric gastroenterologists often prescribe a low-dose tricyclic antidepressant as first-line therapy, but we discourage this. TCAs lack efficacy in pediatric depression and pose a greater risk of side effects and safety concerns than SSRIs.¹⁸

Other agents have been tried for RAP-associated conditions:

Famotidine, a histamine type 2 receptor blocker, may reduce pain in children with dyspepsia and RAP.¹⁹

Peppermint oil reduced abdominal pain in one study of children with IBS but had little effect on other symptoms.²⁰

Medications such as alosetron and tegaserod that interrupt serotonergic neurotransmission in the gut have shown benefit in adults with IBS but have not been studied in children.

Psychotherapy. A few small studies suggest that cognitive-behavioral therapies (CBT) are helpful in RAP, but CBT may be difficult to deliver in medical settings.^21,22 A simplified “rehabilitative” approach that incorporates CBT principles involves having the clinician and patient view RAP as a challenge to be overcome, rather than a burden to be endured. Such an approach emphasizes the child’s fundamental strength and adaptability rather than vulnerabilities.

The goal of therapy is redirected from finding a cure to coping with and overcoming the problem. This approach challenges the notion that the child cannot resume normal function until the pain is completely gone. It encourages active, problem-focused coping, and discourages passive acceptance—which is associated with greater symptom burden and functional impairment.

Work with parents to reinforce the child’s health-promoting behaviors and minimize negative and social reinforcements (secondary gain) associated with RAP. Advise parents to:

• encourage and reward full school attendance
• avoid home-bound instruction
• expect the child to function despite physical distress
• insist that the child perform age-appropriate household chores and other responsibilities.

Self-management skills—such as relaxation training, hypnosis, biofeedback, and guided imagery—may help reduce pain and manage physiologic arousal.¹⁶ Deception strategies such as placebo or sham interventions are unethical and impractical.

Related resources

• Campo JV. Functional recurrent abdominal pain in children and adolescents. Digestive Health Matters 2003;12(3):15-7.
• International Foundation for Functional Gastrointestinal Disorders. www.iffgd.org
• University of Pittsburgh. Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders. www.moodykids.org

Drug brand names

• Alosetron • Lotronex
• Citalopram • Celexa
• Clonazepam • Klonopin
• Escitalopram • Lexapro
• Famotidine • Pepcid
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Sertraline • Zoloft
• Tegaserod • Zelnorm

Disclosure

Dr. Campo’s work has been supported by the National Institute of Mental Health (grant MH01780) and in part by the Advanced Center for Interventions and Services Research on Early Onset Mood and Anxiety Disorders (grant MH66371). He also receives grants from Forest Pharmaceuticals and is a consultant to Eli Lilly and Co.

Ms. A, age 44, fell from a 3-foot stool while reaching for a high kitchen shelf and suffered severe neck flexion. Her initial pain persisted for weeks and then months, resulting in chronic neck pain aggravated by movement.

Over the past year, her doctor has prescribed numerous analgesics and muscle relaxants, including tramadol, hydrocodone, oxycodone, tizanidine, and nonsteroidal anti-inflammatory drugs (NSAIDs). Treatments at a pain clinic have included triggerpoint injections, cervical epidural corticosteroid injection, left-sided cervical medial branch blocks, transcutaneous electrical nerve stimulation, and physical therapy. None provided sustained relief.

During a pain clinic visit, Ms. A wept and said she was tired of living with pain. She acknowledged depression and agreed to psychiatric consultation.

As in Ms. A’s case, physicians often refer patients with chronic pain and affective symptoms for psychiatric evaluation. These patients are often fearful, angry, and suspicious of any suggestion that their physical discomfort has a psychiatric component. They typically believe their pain had a clear onset and therefore should have an end point. Many have experienced unproductive specialty evaluations and failed treatments.

To help you overcome these obstacles when treating patients with chronic pain and depression, we discuss:

• strategies to gain patients’ trust and build a therapeutic alliance
• how to assess their pain, depression, and suicide risk
• the role of psychotherapy in treating chronic pain
• and evidence for choosing effective, nonaddicting medications.

Psychiatric evaluation

Depression and pain are linked psychologically and biochemically, sharing neurotransmitters involved in both nociceptive pathways and mood, especially serotonin and norepinephrine.^1,2 One-third to one-half of patients with chronic pain report comorbid depression,³ and more than one-half of depressed patients presenting to primary care physicians report only somatic symptoms—various pain complaints among the most common.^4,5

Primary care doctors tend to refer chronic pain and depression cases to psychiatrists when:

• patients are preoccupied with medication, have not followed treatment recommendations, or do not respond to treatment as expected
• extensive medical evaluations reveal few or equivocal findings
• somatic complaints are vague and diffuse, or there is marked disparity between pain complaints/disability and objective findings.^6,7

Assessing pain. In the initial assessment, validate the patient’s pain experience by asking about the location, quality, and severity of pain. The visual analogue scale (VAS) is commonly used to measure pain severity. The patient marks a spot on a line from “no pain” to “worst possible pain,” or—on a numbered VAS—from 0 (no pain) to 10 (extreme pain). The least and most severe pain over the preceding month can be ranked as baseline values.⁸

Be sensitive to the patient’s fear that you will attribute the pain to psychosocial issues or imply that “the pain is in your head.” Emphasize that you intend to evaluate the “whole person,” not just the part that hurts. Focus on how the pain affects the patient’s lifestyle—rather than its cause—and explore medication use patterns.

Assessing depression. The word “depression” is emotionally charged for chronic pain patients, who view affective symptoms—if they acknowledge them at all—as secondary to pain. They may strongly resist treatment for anything but pain. One way to defuse this defensiveness is to avoid attributing the pain to stress or depression.

Begin by assessing vegetative symptoms, which overlap in chronic pain and depression. The Beck Depression Inventory-II (Beck-II) may be a useful screening tool in a busy practice; the short form (13 questions) takes about 5 minutes to complete.⁹

Explore cognitive and behavioral symptoms such as concentration, pleasure and interest level, activity, and self-esteem. Review the chronology of pain onset, mood changes, and stressors (proximate, remote, and cumulative).

Seek clues to endogenous factors by asking about past affective episodes, response to antidepressants, and family history of psychopathology. Substances that may induce depression include reserpine, interferon, and antiparkinsonian agents. Screen for potential organic mood disorders, such as depression secondary to hypothyroidism, corticosteroid use, Parkinson’s disease, lupus, HIV infection, or cerebrovascular disease. Where appropriate, obtain collateral information from family or friends.

Assessing suicide risk. Chronic pain patients may be at greater risk of suicide than the general population. Besides pain, other risk factors for suicide—such as major depression, anxiety disorders, alcohol/substance abuse, sleep disturbances, male gender, diminished social support, and recent loss—are common among these patients.^10,11

Screen chronic pain patients with suicidal ideation for these risk factors. Interventions include:

• aggressively treat associated depression, anxiety, or insomnia
• elicit support from family or other caregivers
• pay close attention to talk about suicide
• hospitalize when necessary
• and, of course, treat pain.

Case continued: No stranger to depression

Ms. A’s psychiatric assessments revealed a pain severity ranking of 9 on a 1-to-10 scale, frequent crying, hopelessness, disrupted sleep, low energy, limited ability to concentrate, and fleeting suicidal thoughts. Her history included counseling during her first marriage and severe depression after separation from her second husband 3 years ago. An 8-week trial of fluoxetine, 20 mg/d, did not improve her depression then.

On examination, she displayed obvious pain behavior, constantly shifting her neck position and moving about the room. Her affect was tearful and her mood depressed. She was taking the NSAID celecoxib, 100 mg bid, and the skeletal muscle relaxant tizanidine, 4 mg tid. She was no longer using opioids and had no history of alcohol or illicit drug abuse.

Based on this assessment, the psychiatrist diagnosed Ms. A as having pain disorder with medical and psychological features, including symptom amplification and depression.

Table 1

4 treatment goals for patients with chronic pain and depression

Educating the patient

As part of your assessment, explain the reciprocal effects of depression and pain. Acknowledge that:

• chronic pain is different from acute pain, although the patient’s pain experience is the same
• treatment often becomes part of the problem in chronic pain.

Doctors tend to apply acute pain treatments chronically, risking long-term effects of polypharmacy to achieve short-term relief. Depressed patients may be more likely than nondepressed patients to receive opioids for chronic pain,¹² and opioids and benzodiazepines may have depressive effects, as reflected by DSM-IV-TR’s inclusion of criteria for “opioid-induced mood disorder” and “sedative-, hypnotic-, or anxiolytic-induced mood disorder.”

To reduce patients’ resistance to antidepressants, reiterate any history of cumulative stressors and affective episodes unrelated to pain. Try using an analogy, such as “stress and pain are like waves on a rock” that eventually damage mood and coping mechanisms, or depression complicating pain is like having “too much on one’s plate.”

Finally, help patients understand that chronic pain is managed, not cured. Encourage them to set treatment goals beyond reducing pain (Table 1) and to make the transition from “patient with pain” to “client managing pain.”

Table 2

Dosing antidepressants and anticonvulsants
for chronic pain and depression

Prescribing principles

Before adding any new pain medications, consider reducing dosages or discontinuing opioids or benzodiazepines and other substances the patient may be taking. Opioid use is associated with risks of dependence, addiction, and side effects including somnolence, cognitive impairment, and reduced activity that amplify depressive symptoms.

Benzodiazepines can generally be tapered by 10% per day, although you may need to extend the final taper over 3 to 4 days or longer, depending upon chronicity of use. Opioids may be tapered by 20% over 5 to 7 days. Breakthrough doses may be needed for marked withdrawal symptoms. Converting to longer half-life agents—such as clonazepam for benzodiazepines or methadone for opioids—often aids tapering, although other agents and strategies exist.¹³

To gauge patient attempts at self-medication, monitor use of alcohol or illicit drugs with urine screening. For patients with a substantial history of substance abuse or positive toxicology screens, monitor randomly every 2 to 4 weeks.

On the other hand, undertreated pain also may impair mood and function.¹ If pain and mood improve and problematic drug-related behaviors resolve with increased opioid analgesia, consider maintaining opioids with regular re-evaluation of mood, coping, and medication adherence.¹¹ Transfer from immediate-release to controlled-release opioids to reduce dosing frequency, clockwatching, and the likelihood of inter-dose pain escalation. In general, maintain and optimize the dosage of nonaddictive analgesics such as NSAIDs, anticonvulsants, or antidepressants.

Case continued: Switching medication

The psychiatrist started Ms. A on nortriptyline, 25 mg at bedtime, to be increased after 3 nights to 50 mg at bedtime. Tizanidine, which had been ineffective, was discontinued to reduce the risk of xerostomia and oversedation in combination with nortriptyline. If tolerated, nortriptyline was to be further increased by 25 mg every 3 days to an initial target dosage of 100 mg at bedtime. The psychiatrist explained to Ms. A that it might take 4 to 6 weeks to gauge the medication’s efficacy.

Psychoeducation addressed the importance of stress reduction, prioritizing commitments, and setting limits on other people’s expectations. The door was left open to future psychotherapeutic exploration of past cumulative stressors.

Because antidepressants may provide an analgesic effect,^6,14 they are often used to treat affective symptoms in chronic pain. Headache and neuralgia tend to respond to antidepressants more robustly than do arthritis and low-back pain. Although some patients respond to low-dose antidepressants, a definitive trial requires full doses for 6 to 8 weeks (Table 2).

Matching a patient’s symptoms with medication side effects is useful when choosing antidepressants (Table 3). So-called “adverse” effects may have a corresponding benefit, depending on the clinical presentation. For example, a moreactivating antidepressant—such as the selective serotonin reuptake inhibitor (SSRI) fluoxetine—may help a patient with fatigue, whereas a moresedating agent—such as a tricyclic antidepressant (TCA) or mirtazapine—may improve sleep for a patient with insomnia.

Psychosocial therapies such as cognitive-behavioral therapy (CBT) or relaxation training (Table 4) may help patients with chronic pain to:

• process covert emotions such as fear and anger as well as guilt, loss, and disability
• reduce somatic preoccupation that is aggravating the pain
• adhere to treatment.

Evidence strongly supports using relaxation techniques to reduce chronic pain in many medical conditions and hypnosis to ameliorate cancer pain. CBT and biofeedback appear moderately effective in relieving chronic pain.¹⁵ CBT is significantly more effective than waiting list control conditions for relieving chronic nonheadache pain in measures of pain experience, mood/affect, cognitive coping and appraisal, pain behavior and activity level, and social role functioning.¹⁶

Pain and opioid medications can impair concentration and affective processing, so initial psychotherapy may need to be supportive while you provide other treatments and simplify medication regimens. Eventually the patient may be ready to address underlying issues that may be contributing to the pain syndrome, such as a history of abuse. However, it is important to address this potentially destabilizing subject only after carefully gauging a patient’s defenses and readiness.

Case continued: A bump in the road

The psychiatrist saw Ms. A 18 months later. Interim history revealed that her pain and mood improved on nortriptyline, 100 mg at bedtime. When she stopped taking nortriptyline 5 months earlier, her neck pain increased and she experienced a “deep blue mood.” Her physician restarted the nortriptyline.

At follow up, Ms. A reported no depressive symptoms and very little neck pain. The psychiatrist discussed with her depression’s relapse rate and the importance of continuing antidepressant therapy. As Ms. A was feeling much better and functioning normally, the psychiatrist decided additional psychotherapeutic intervention was not necessary.

Antidepressant options

TCAs provide analgesia via descending regulatory pathways by inhibiting serotonin and norepinephrine reuptake.¹⁷ When using TCAs for chronic pain, start with 10 to 25 mg at bedtime and increase by 10 to 25 mg every 3 to 7 days as tolerated. Increase incrementally until the pain responds or to the full antidepressant dosage (Table 2). Drug levels (when available) can help you provide an appropriate trial and monitor the patient’s adherence.

If the pain does not respond after 6 to 8 weeks, consider switching to another dual-action agent such as venlafaxine or to an SSRI.

SNRIs. Venlafaxine is a serotonin and norepineph-rine reuptake inhibitor (SNRI) with less-troublesome side effects than TCAs. It is structurally similar to tramadol¹⁸ and has combined serotonin and norepinephrine inhibition at dosages >75 mg/d. Although venlafaxine is not indicated for chronic pain, some studies have suggested possible benefits, including long-term analgesia, reduced polyneuropathic pain, and migraine prophylaxis.^19-21 Venlafaxine may be a reasonable first or second choice for treating depression in patients with chronic pain, especially headache.¹⁴

Duloxetine—another SNRI—awaits FDA approval. Some studies have suggested that duloxetine improves painful physical symptoms as well as mood and functioning in major depression.²²

SSRIs may be effective for certain types of pain, but the evidence is conflicting. Results of 41controlled trials support TCAs’ analgesic efficacy for neuropathic pain, headache, and central and post-stroke pain, whereas SSRIs’ analgesic efficacy varies from study to study. Comparisons of TCAs and SSRIs as analgesics uniformly show TCAs to be more effective, with the SSRIs often showing no analgesic effect.

Of three controlled trials of SSRIs for diabetic neuropathy, one showed fluoxetine similar to placebo, and two smaller studies showed paroxetine and citalopram more effective than placebo. Fluoxetine has shown analgesic effect for fibromyalgia in one study, but no effect in another. Citalopram showed no analgesic effect for fibromyalgia in another study.²³

A prospective, double-blind study comparing fluoxetine, sertraline, paroxetine, and venlafaxine for migraines reported moderate to significant improvement in less than one-half of SSRI-treated patients vs two-thirds of venlafaxine-treated patients.²¹ SSRIs are no longer recognized by the International Headache Society as primary preventative medications for migraine.

Fluoxetine may help chronic daily headache, and paroxetine and citalopram may be useful for diabetic neuropathy. However, one cannot generalize that all SSRIs are similarly effective as analgesics.¹⁴

SSRIs have fewer side effects than TCAs and are less dangerous in overdose. In general, however, SSRIs are a second-line treatment for pain, to be used when dual-action agents pose disadvantageous side effects (Table 3) or have been poorly tolerated or ineffective.

Table 3

Antidepressant side effects:
Limitations and potential benefits in chronic pain

Table 4

How psychosocial therapies can help treat chronic pain and depression

Monoamine oxidase inhibitors (MAOIs) may have some efficacy for neuropathy and headache, but the need for a tyramine-free diet and potential for drug-drug interactions limit their usefulness. Co-administering an MAOI and meperidine is always contraindicated, as this combination can produce fever, delirium, seizures, circulatory collapse, and death. Similarly, avoid using an MAOI with any other antidepressant.

Others. Evidence is very limited on using other antidepressants such as trazodone, nefazodone, bupropion, and mirtazapine in chronic pain:

• Trazodone may help pediatric migraine, but it is not a consistent analgesic and may not be well-tolerated.
• Case reports suggest bupropion may help with headaches and chronic low-back pain.¹⁴
• Mirtazapine and trazodone may be useful adjuncts for treating insomnia in depressed patients with chronic pain.

Other options

Anticonvulsants appear useful for neuropathic pain and are appropriate for chronic pain patients who cannot tolerate TCAs.²⁴ Like TCAs, anticonvulsants are not addictive. Unlike TCAs, anticonvulsants may help stabilize other affective illnesses that may coexist with chronic pain, including bipolar disorder, schizoaffective disorder, and impulsivity/aggression related to dementia or personality disorder.⁶ If the starting dosage is not effective within 1 week, increase gradually every 2 to 3 days to target dosages comparable to those for anticonvulsant efficacy.

Carbamazepine and gabapentin are recommended first-line medications for neuropathy. Carbamazepine is indicated for treating trigeminal neuralgia, although its cytochrome P-450 3A3/4 isoenzyme induction may reduce serum levels of acetaminophen, opioids, and oral contraceptives. Gabapentin, although not clearly beneficial for bipolar disorder, has anxiolytic effects and a benign side-effect profile, which may help patients with chronic pain.

Valproate can help prevent migraines. Clonazepam can help reduce anxiety and restless legs syndrome but may be habituating. Anticonvulsants’ common adverse effects include sedation, GI upset, dizziness, and fatigue.

Lithium has known efficacy for mood stabilization in bipolar disorder and can ameliorate cluster headaches.

Antipsychotics. Evidence is sparse on whether antipsychotics have analgesic activity. Their side effects generally limit their usefulness to treating pain in patients with psychosis or delirium.⁶

Stimulants such as dextroamphetamine and methylphenidate can be helpful adjuncts for treating depression, especially for medical inpatients who require a rapid therapeutic response. Stimulants may reduce fatigue or excessive sedation and improve concentration in patients receiving opioids for chronic pain. They also may have analgesic effects when combined with opioids. Potential adverse effects include appetite suppression, anxiety or agitation, confusion, tics, and addiction.⁶

Precautions. The muscle relaxant carisoprodol is associated with potential dependence and withdrawal. Cyclobenzaprine, another muscle relaxant, has a TCA-like structure and can be lethal in overdose. Baclofen can be useful for chronic pain related to spasticity, although psychotic depression and mania have been reported with abrupt withdrawal.⁶

Related resources

• American Academy of Pain Medicine. www.painmed.org/
• American Academy of Pain Management. www.aapainmanage.org
• Pain.com: continuing medical education for anesthesiology professionals. www.pain.com/index.cfm
• Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985;13:345-56

Drug brand names

• Amitriptyline • Elavil
• Baclofen • Lioresal
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Carisoprodol • Soma
• Celecoxib • Celebrex
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Dihydrocodeine • Synalgos-DC
• Doxepin • Sinequan
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Hydrocodone • Vicodin, Lortab
• Imipramine • Tofranil
• Lithium • Eskalith CR, Lithobid
• Maprotiline • Ludiomil
• Meperidine • Demerol
• Methadone • Dolophine
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nortriptyline • Pamelor
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tizanidine • Zanaflex
• Tramadol • Ultram
• Trazodone • Desyrel
• Valproate • Depakote
• Venlafaxine • Effexor, Effexor XR

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. A, age 44, fell from a 3-foot stool while reaching for a high kitchen shelf and suffered severe neck flexion. Her initial pain persisted for weeks and then months, resulting in chronic neck pain aggravated by movement.

Over the past year, her doctor has prescribed numerous analgesics and muscle relaxants, including tramadol, hydrocodone, oxycodone, tizanidine, and nonsteroidal anti-inflammatory drugs (NSAIDs). Treatments at a pain clinic have included triggerpoint injections, cervical epidural corticosteroid injection, left-sided cervical medial branch blocks, transcutaneous electrical nerve stimulation, and physical therapy. None provided sustained relief.

During a pain clinic visit, Ms. A wept and said she was tired of living with pain. She acknowledged depression and agreed to psychiatric consultation.

As in Ms. A’s case, physicians often refer patients with chronic pain and affective symptoms for psychiatric evaluation. These patients are often fearful, angry, and suspicious of any suggestion that their physical discomfort has a psychiatric component. They typically believe their pain had a clear onset and therefore should have an end point. Many have experienced unproductive specialty evaluations and failed treatments.

To help you overcome these obstacles when treating patients with chronic pain and depression, we discuss:

• strategies to gain patients’ trust and build a therapeutic alliance
• how to assess their pain, depression, and suicide risk
• the role of psychotherapy in treating chronic pain
• and evidence for choosing effective, nonaddicting medications.

Psychiatric evaluation

Depression and pain are linked psychologically and biochemically, sharing neurotransmitters involved in both nociceptive pathways and mood, especially serotonin and norepinephrine.^1,2 One-third to one-half of patients with chronic pain report comorbid depression,³ and more than one-half of depressed patients presenting to primary care physicians report only somatic symptoms—various pain complaints among the most common.^4,5

Primary care doctors tend to refer chronic pain and depression cases to psychiatrists when:

• patients are preoccupied with medication, have not followed treatment recommendations, or do not respond to treatment as expected
• extensive medical evaluations reveal few or equivocal findings
• somatic complaints are vague and diffuse, or there is marked disparity between pain complaints/disability and objective findings.^6,7

Assessing pain. In the initial assessment, validate the patient’s pain experience by asking about the location, quality, and severity of pain. The visual analogue scale (VAS) is commonly used to measure pain severity. The patient marks a spot on a line from “no pain” to “worst possible pain,” or—on a numbered VAS—from 0 (no pain) to 10 (extreme pain). The least and most severe pain over the preceding month can be ranked as baseline values.⁸

Be sensitive to the patient’s fear that you will attribute the pain to psychosocial issues or imply that “the pain is in your head.” Emphasize that you intend to evaluate the “whole person,” not just the part that hurts. Focus on how the pain affects the patient’s lifestyle—rather than its cause—and explore medication use patterns.

Assessing depression. The word “depression” is emotionally charged for chronic pain patients, who view affective symptoms—if they acknowledge them at all—as secondary to pain. They may strongly resist treatment for anything but pain. One way to defuse this defensiveness is to avoid attributing the pain to stress or depression.

Begin by assessing vegetative symptoms, which overlap in chronic pain and depression. The Beck Depression Inventory-II (Beck-II) may be a useful screening tool in a busy practice; the short form (13 questions) takes about 5 minutes to complete.⁹

Explore cognitive and behavioral symptoms such as concentration, pleasure and interest level, activity, and self-esteem. Review the chronology of pain onset, mood changes, and stressors (proximate, remote, and cumulative).

Seek clues to endogenous factors by asking about past affective episodes, response to antidepressants, and family history of psychopathology. Substances that may induce depression include reserpine, interferon, and antiparkinsonian agents. Screen for potential organic mood disorders, such as depression secondary to hypothyroidism, corticosteroid use, Parkinson’s disease, lupus, HIV infection, or cerebrovascular disease. Where appropriate, obtain collateral information from family or friends.

Assessing suicide risk. Chronic pain patients may be at greater risk of suicide than the general population. Besides pain, other risk factors for suicide—such as major depression, anxiety disorders, alcohol/substance abuse, sleep disturbances, male gender, diminished social support, and recent loss—are common among these patients.^10,11

Screen chronic pain patients with suicidal ideation for these risk factors. Interventions include:

• aggressively treat associated depression, anxiety, or insomnia
• elicit support from family or other caregivers
• pay close attention to talk about suicide
• hospitalize when necessary
• and, of course, treat pain.

Case continued: No stranger to depression

Ms. A’s psychiatric assessments revealed a pain severity ranking of 9 on a 1-to-10 scale, frequent crying, hopelessness, disrupted sleep, low energy, limited ability to concentrate, and fleeting suicidal thoughts. Her history included counseling during her first marriage and severe depression after separation from her second husband 3 years ago. An 8-week trial of fluoxetine, 20 mg/d, did not improve her depression then.

On examination, she displayed obvious pain behavior, constantly shifting her neck position and moving about the room. Her affect was tearful and her mood depressed. She was taking the NSAID celecoxib, 100 mg bid, and the skeletal muscle relaxant tizanidine, 4 mg tid. She was no longer using opioids and had no history of alcohol or illicit drug abuse.

Based on this assessment, the psychiatrist diagnosed Ms. A as having pain disorder with medical and psychological features, including symptom amplification and depression.

Table 1

4 treatment goals for patients with chronic pain and depression

Educating the patient

As part of your assessment, explain the reciprocal effects of depression and pain. Acknowledge that:

• chronic pain is different from acute pain, although the patient’s pain experience is the same
• treatment often becomes part of the problem in chronic pain.

Doctors tend to apply acute pain treatments chronically, risking long-term effects of polypharmacy to achieve short-term relief. Depressed patients may be more likely than nondepressed patients to receive opioids for chronic pain,¹² and opioids and benzodiazepines may have depressive effects, as reflected by DSM-IV-TR’s inclusion of criteria for “opioid-induced mood disorder” and “sedative-, hypnotic-, or anxiolytic-induced mood disorder.”

To reduce patients’ resistance to antidepressants, reiterate any history of cumulative stressors and affective episodes unrelated to pain. Try using an analogy, such as “stress and pain are like waves on a rock” that eventually damage mood and coping mechanisms, or depression complicating pain is like having “too much on one’s plate.”

Finally, help patients understand that chronic pain is managed, not cured. Encourage them to set treatment goals beyond reducing pain (Table 1) and to make the transition from “patient with pain” to “client managing pain.”

Table 2

Dosing antidepressants and anticonvulsants
for chronic pain and depression

Prescribing principles

Before adding any new pain medications, consider reducing dosages or discontinuing opioids or benzodiazepines and other substances the patient may be taking. Opioid use is associated with risks of dependence, addiction, and side effects including somnolence, cognitive impairment, and reduced activity that amplify depressive symptoms.

Benzodiazepines can generally be tapered by 10% per day, although you may need to extend the final taper over 3 to 4 days or longer, depending upon chronicity of use. Opioids may be tapered by 20% over 5 to 7 days. Breakthrough doses may be needed for marked withdrawal symptoms. Converting to longer half-life agents—such as clonazepam for benzodiazepines or methadone for opioids—often aids tapering, although other agents and strategies exist.¹³

To gauge patient attempts at self-medication, monitor use of alcohol or illicit drugs with urine screening. For patients with a substantial history of substance abuse or positive toxicology screens, monitor randomly every 2 to 4 weeks.

On the other hand, undertreated pain also may impair mood and function.¹ If pain and mood improve and problematic drug-related behaviors resolve with increased opioid analgesia, consider maintaining opioids with regular re-evaluation of mood, coping, and medication adherence.¹¹ Transfer from immediate-release to controlled-release opioids to reduce dosing frequency, clockwatching, and the likelihood of inter-dose pain escalation. In general, maintain and optimize the dosage of nonaddictive analgesics such as NSAIDs, anticonvulsants, or antidepressants.

Case continued: Switching medication

The psychiatrist started Ms. A on nortriptyline, 25 mg at bedtime, to be increased after 3 nights to 50 mg at bedtime. Tizanidine, which had been ineffective, was discontinued to reduce the risk of xerostomia and oversedation in combination with nortriptyline. If tolerated, nortriptyline was to be further increased by 25 mg every 3 days to an initial target dosage of 100 mg at bedtime. The psychiatrist explained to Ms. A that it might take 4 to 6 weeks to gauge the medication’s efficacy.

Psychoeducation addressed the importance of stress reduction, prioritizing commitments, and setting limits on other people’s expectations. The door was left open to future psychotherapeutic exploration of past cumulative stressors.

Because antidepressants may provide an analgesic effect,^6,14 they are often used to treat affective symptoms in chronic pain. Headache and neuralgia tend to respond to antidepressants more robustly than do arthritis and low-back pain. Although some patients respond to low-dose antidepressants, a definitive trial requires full doses for 6 to 8 weeks (Table 2).

Matching a patient’s symptoms with medication side effects is useful when choosing antidepressants (Table 3). So-called “adverse” effects may have a corresponding benefit, depending on the clinical presentation. For example, a moreactivating antidepressant—such as the selective serotonin reuptake inhibitor (SSRI) fluoxetine—may help a patient with fatigue, whereas a moresedating agent—such as a tricyclic antidepressant (TCA) or mirtazapine—may improve sleep for a patient with insomnia.

Psychosocial therapies such as cognitive-behavioral therapy (CBT) or relaxation training (Table 4) may help patients with chronic pain to:

• process covert emotions such as fear and anger as well as guilt, loss, and disability
• reduce somatic preoccupation that is aggravating the pain
• adhere to treatment.

Evidence strongly supports using relaxation techniques to reduce chronic pain in many medical conditions and hypnosis to ameliorate cancer pain. CBT and biofeedback appear moderately effective in relieving chronic pain.¹⁵ CBT is significantly more effective than waiting list control conditions for relieving chronic nonheadache pain in measures of pain experience, mood/affect, cognitive coping and appraisal, pain behavior and activity level, and social role functioning.¹⁶

Pain and opioid medications can impair concentration and affective processing, so initial psychotherapy may need to be supportive while you provide other treatments and simplify medication regimens. Eventually the patient may be ready to address underlying issues that may be contributing to the pain syndrome, such as a history of abuse. However, it is important to address this potentially destabilizing subject only after carefully gauging a patient’s defenses and readiness.

Case continued: A bump in the road

The psychiatrist saw Ms. A 18 months later. Interim history revealed that her pain and mood improved on nortriptyline, 100 mg at bedtime. When she stopped taking nortriptyline 5 months earlier, her neck pain increased and she experienced a “deep blue mood.” Her physician restarted the nortriptyline.

At follow up, Ms. A reported no depressive symptoms and very little neck pain. The psychiatrist discussed with her depression’s relapse rate and the importance of continuing antidepressant therapy. As Ms. A was feeling much better and functioning normally, the psychiatrist decided additional psychotherapeutic intervention was not necessary.

Antidepressant options

TCAs provide analgesia via descending regulatory pathways by inhibiting serotonin and norepinephrine reuptake.¹⁷ When using TCAs for chronic pain, start with 10 to 25 mg at bedtime and increase by 10 to 25 mg every 3 to 7 days as tolerated. Increase incrementally until the pain responds or to the full antidepressant dosage (Table 2). Drug levels (when available) can help you provide an appropriate trial and monitor the patient’s adherence.

If the pain does not respond after 6 to 8 weeks, consider switching to another dual-action agent such as venlafaxine or to an SSRI.

SNRIs. Venlafaxine is a serotonin and norepineph-rine reuptake inhibitor (SNRI) with less-troublesome side effects than TCAs. It is structurally similar to tramadol¹⁸ and has combined serotonin and norepinephrine inhibition at dosages >75 mg/d. Although venlafaxine is not indicated for chronic pain, some studies have suggested possible benefits, including long-term analgesia, reduced polyneuropathic pain, and migraine prophylaxis.^19-21 Venlafaxine may be a reasonable first or second choice for treating depression in patients with chronic pain, especially headache.¹⁴

Duloxetine—another SNRI—awaits FDA approval. Some studies have suggested that duloxetine improves painful physical symptoms as well as mood and functioning in major depression.²²

SSRIs may be effective for certain types of pain, but the evidence is conflicting. Results of 41controlled trials support TCAs’ analgesic efficacy for neuropathic pain, headache, and central and post-stroke pain, whereas SSRIs’ analgesic efficacy varies from study to study. Comparisons of TCAs and SSRIs as analgesics uniformly show TCAs to be more effective, with the SSRIs often showing no analgesic effect.

Of three controlled trials of SSRIs for diabetic neuropathy, one showed fluoxetine similar to placebo, and two smaller studies showed paroxetine and citalopram more effective than placebo. Fluoxetine has shown analgesic effect for fibromyalgia in one study, but no effect in another. Citalopram showed no analgesic effect for fibromyalgia in another study.²³

A prospective, double-blind study comparing fluoxetine, sertraline, paroxetine, and venlafaxine for migraines reported moderate to significant improvement in less than one-half of SSRI-treated patients vs two-thirds of venlafaxine-treated patients.²¹ SSRIs are no longer recognized by the International Headache Society as primary preventative medications for migraine.

Fluoxetine may help chronic daily headache, and paroxetine and citalopram may be useful for diabetic neuropathy. However, one cannot generalize that all SSRIs are similarly effective as analgesics.¹⁴

SSRIs have fewer side effects than TCAs and are less dangerous in overdose. In general, however, SSRIs are a second-line treatment for pain, to be used when dual-action agents pose disadvantageous side effects (Table 3) or have been poorly tolerated or ineffective.

Table 3

Antidepressant side effects:
Limitations and potential benefits in chronic pain

Table 4

How psychosocial therapies can help treat chronic pain and depression

Monoamine oxidase inhibitors (MAOIs) may have some efficacy for neuropathy and headache, but the need for a tyramine-free diet and potential for drug-drug interactions limit their usefulness. Co-administering an MAOI and meperidine is always contraindicated, as this combination can produce fever, delirium, seizures, circulatory collapse, and death. Similarly, avoid using an MAOI with any other antidepressant.

Others. Evidence is very limited on using other antidepressants such as trazodone, nefazodone, bupropion, and mirtazapine in chronic pain:

• Trazodone may help pediatric migraine, but it is not a consistent analgesic and may not be well-tolerated.
• Case reports suggest bupropion may help with headaches and chronic low-back pain.¹⁴
• Mirtazapine and trazodone may be useful adjuncts for treating insomnia in depressed patients with chronic pain.

Other options

Anticonvulsants appear useful for neuropathic pain and are appropriate for chronic pain patients who cannot tolerate TCAs.²⁴ Like TCAs, anticonvulsants are not addictive. Unlike TCAs, anticonvulsants may help stabilize other affective illnesses that may coexist with chronic pain, including bipolar disorder, schizoaffective disorder, and impulsivity/aggression related to dementia or personality disorder.⁶ If the starting dosage is not effective within 1 week, increase gradually every 2 to 3 days to target dosages comparable to those for anticonvulsant efficacy.

Carbamazepine and gabapentin are recommended first-line medications for neuropathy. Carbamazepine is indicated for treating trigeminal neuralgia, although its cytochrome P-450 3A3/4 isoenzyme induction may reduce serum levels of acetaminophen, opioids, and oral contraceptives. Gabapentin, although not clearly beneficial for bipolar disorder, has anxiolytic effects and a benign side-effect profile, which may help patients with chronic pain.

Valproate can help prevent migraines. Clonazepam can help reduce anxiety and restless legs syndrome but may be habituating. Anticonvulsants’ common adverse effects include sedation, GI upset, dizziness, and fatigue.

Lithium has known efficacy for mood stabilization in bipolar disorder and can ameliorate cluster headaches.

Antipsychotics. Evidence is sparse on whether antipsychotics have analgesic activity. Their side effects generally limit their usefulness to treating pain in patients with psychosis or delirium.⁶

Stimulants such as dextroamphetamine and methylphenidate can be helpful adjuncts for treating depression, especially for medical inpatients who require a rapid therapeutic response. Stimulants may reduce fatigue or excessive sedation and improve concentration in patients receiving opioids for chronic pain. They also may have analgesic effects when combined with opioids. Potential adverse effects include appetite suppression, anxiety or agitation, confusion, tics, and addiction.⁶

Precautions. The muscle relaxant carisoprodol is associated with potential dependence and withdrawal. Cyclobenzaprine, another muscle relaxant, has a TCA-like structure and can be lethal in overdose. Baclofen can be useful for chronic pain related to spasticity, although psychotic depression and mania have been reported with abrupt withdrawal.⁶

Related resources

• American Academy of Pain Medicine. www.painmed.org/
• American Academy of Pain Management. www.aapainmanage.org
• Pain.com: continuing medical education for anesthesiology professionals. www.pain.com/index.cfm
• Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985;13:345-56

Drug brand names

• Amitriptyline • Elavil
• Baclofen • Lioresal
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Carisoprodol • Soma
• Celecoxib • Celebrex
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Dihydrocodeine • Synalgos-DC
• Doxepin • Sinequan
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Hydrocodone • Vicodin, Lortab
• Imipramine • Tofranil
• Lithium • Eskalith CR, Lithobid
• Maprotiline • Ludiomil
• Meperidine • Demerol
• Methadone • Dolophine
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nortriptyline • Pamelor
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tizanidine • Zanaflex
• Tramadol • Ultram
• Trazodone • Desyrel
• Valproate • Depakote
• Venlafaxine • Effexor, Effexor XR

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. A, age 44, fell from a 3-foot stool while reaching for a high kitchen shelf and suffered severe neck flexion. Her initial pain persisted for weeks and then months, resulting in chronic neck pain aggravated by movement.

Over the past year, her doctor has prescribed numerous analgesics and muscle relaxants, including tramadol, hydrocodone, oxycodone, tizanidine, and nonsteroidal anti-inflammatory drugs (NSAIDs). Treatments at a pain clinic have included triggerpoint injections, cervical epidural corticosteroid injection, left-sided cervical medial branch blocks, transcutaneous electrical nerve stimulation, and physical therapy. None provided sustained relief.

During a pain clinic visit, Ms. A wept and said she was tired of living with pain. She acknowledged depression and agreed to psychiatric consultation.

As in Ms. A’s case, physicians often refer patients with chronic pain and affective symptoms for psychiatric evaluation. These patients are often fearful, angry, and suspicious of any suggestion that their physical discomfort has a psychiatric component. They typically believe their pain had a clear onset and therefore should have an end point. Many have experienced unproductive specialty evaluations and failed treatments.

To help you overcome these obstacles when treating patients with chronic pain and depression, we discuss:

• strategies to gain patients’ trust and build a therapeutic alliance
• how to assess their pain, depression, and suicide risk
• the role of psychotherapy in treating chronic pain
• and evidence for choosing effective, nonaddicting medications.

Psychiatric evaluation

Depression and pain are linked psychologically and biochemically, sharing neurotransmitters involved in both nociceptive pathways and mood, especially serotonin and norepinephrine.^1,2 One-third to one-half of patients with chronic pain report comorbid depression,³ and more than one-half of depressed patients presenting to primary care physicians report only somatic symptoms—various pain complaints among the most common.^4,5

Primary care doctors tend to refer chronic pain and depression cases to psychiatrists when:

• patients are preoccupied with medication, have not followed treatment recommendations, or do not respond to treatment as expected
• extensive medical evaluations reveal few or equivocal findings
• somatic complaints are vague and diffuse, or there is marked disparity between pain complaints/disability and objective findings.^6,7

Assessing pain. In the initial assessment, validate the patient’s pain experience by asking about the location, quality, and severity of pain. The visual analogue scale (VAS) is commonly used to measure pain severity. The patient marks a spot on a line from “no pain” to “worst possible pain,” or—on a numbered VAS—from 0 (no pain) to 10 (extreme pain). The least and most severe pain over the preceding month can be ranked as baseline values.⁸

Be sensitive to the patient’s fear that you will attribute the pain to psychosocial issues or imply that “the pain is in your head.” Emphasize that you intend to evaluate the “whole person,” not just the part that hurts. Focus on how the pain affects the patient’s lifestyle—rather than its cause—and explore medication use patterns.

Assessing depression. The word “depression” is emotionally charged for chronic pain patients, who view affective symptoms—if they acknowledge them at all—as secondary to pain. They may strongly resist treatment for anything but pain. One way to defuse this defensiveness is to avoid attributing the pain to stress or depression.

Begin by assessing vegetative symptoms, which overlap in chronic pain and depression. The Beck Depression Inventory-II (Beck-II) may be a useful screening tool in a busy practice; the short form (13 questions) takes about 5 minutes to complete.⁹

Explore cognitive and behavioral symptoms such as concentration, pleasure and interest level, activity, and self-esteem. Review the chronology of pain onset, mood changes, and stressors (proximate, remote, and cumulative).

Seek clues to endogenous factors by asking about past affective episodes, response to antidepressants, and family history of psychopathology. Substances that may induce depression include reserpine, interferon, and antiparkinsonian agents. Screen for potential organic mood disorders, such as depression secondary to hypothyroidism, corticosteroid use, Parkinson’s disease, lupus, HIV infection, or cerebrovascular disease. Where appropriate, obtain collateral information from family or friends.

Assessing suicide risk. Chronic pain patients may be at greater risk of suicide than the general population. Besides pain, other risk factors for suicide—such as major depression, anxiety disorders, alcohol/substance abuse, sleep disturbances, male gender, diminished social support, and recent loss—are common among these patients.^10,11

Screen chronic pain patients with suicidal ideation for these risk factors. Interventions include:

• aggressively treat associated depression, anxiety, or insomnia
• elicit support from family or other caregivers
• pay close attention to talk about suicide
• hospitalize when necessary
• and, of course, treat pain.

Case continued: No stranger to depression

Ms. A’s psychiatric assessments revealed a pain severity ranking of 9 on a 1-to-10 scale, frequent crying, hopelessness, disrupted sleep, low energy, limited ability to concentrate, and fleeting suicidal thoughts. Her history included counseling during her first marriage and severe depression after separation from her second husband 3 years ago. An 8-week trial of fluoxetine, 20 mg/d, did not improve her depression then.

On examination, she displayed obvious pain behavior, constantly shifting her neck position and moving about the room. Her affect was tearful and her mood depressed. She was taking the NSAID celecoxib, 100 mg bid, and the skeletal muscle relaxant tizanidine, 4 mg tid. She was no longer using opioids and had no history of alcohol or illicit drug abuse.

Based on this assessment, the psychiatrist diagnosed Ms. A as having pain disorder with medical and psychological features, including symptom amplification and depression.

Table 1

4 treatment goals for patients with chronic pain and depression

Educating the patient

As part of your assessment, explain the reciprocal effects of depression and pain. Acknowledge that:

• chronic pain is different from acute pain, although the patient’s pain experience is the same
• treatment often becomes part of the problem in chronic pain.

Doctors tend to apply acute pain treatments chronically, risking long-term effects of polypharmacy to achieve short-term relief. Depressed patients may be more likely than nondepressed patients to receive opioids for chronic pain,¹² and opioids and benzodiazepines may have depressive effects, as reflected by DSM-IV-TR’s inclusion of criteria for “opioid-induced mood disorder” and “sedative-, hypnotic-, or anxiolytic-induced mood disorder.”

To reduce patients’ resistance to antidepressants, reiterate any history of cumulative stressors and affective episodes unrelated to pain. Try using an analogy, such as “stress and pain are like waves on a rock” that eventually damage mood and coping mechanisms, or depression complicating pain is like having “too much on one’s plate.”

Finally, help patients understand that chronic pain is managed, not cured. Encourage them to set treatment goals beyond reducing pain (Table 1) and to make the transition from “patient with pain” to “client managing pain.”

Table 2

Dosing antidepressants and anticonvulsants
for chronic pain and depression

Prescribing principles

Before adding any new pain medications, consider reducing dosages or discontinuing opioids or benzodiazepines and other substances the patient may be taking. Opioid use is associated with risks of dependence, addiction, and side effects including somnolence, cognitive impairment, and reduced activity that amplify depressive symptoms.

Benzodiazepines can generally be tapered by 10% per day, although you may need to extend the final taper over 3 to 4 days or longer, depending upon chronicity of use. Opioids may be tapered by 20% over 5 to 7 days. Breakthrough doses may be needed for marked withdrawal symptoms. Converting to longer half-life agents—such as clonazepam for benzodiazepines or methadone for opioids—often aids tapering, although other agents and strategies exist.¹³

To gauge patient attempts at self-medication, monitor use of alcohol or illicit drugs with urine screening. For patients with a substantial history of substance abuse or positive toxicology screens, monitor randomly every 2 to 4 weeks.

On the other hand, undertreated pain also may impair mood and function.¹ If pain and mood improve and problematic drug-related behaviors resolve with increased opioid analgesia, consider maintaining opioids with regular re-evaluation of mood, coping, and medication adherence.¹¹ Transfer from immediate-release to controlled-release opioids to reduce dosing frequency, clockwatching, and the likelihood of inter-dose pain escalation. In general, maintain and optimize the dosage of nonaddictive analgesics such as NSAIDs, anticonvulsants, or antidepressants.

Case continued: Switching medication

The psychiatrist started Ms. A on nortriptyline, 25 mg at bedtime, to be increased after 3 nights to 50 mg at bedtime. Tizanidine, which had been ineffective, was discontinued to reduce the risk of xerostomia and oversedation in combination with nortriptyline. If tolerated, nortriptyline was to be further increased by 25 mg every 3 days to an initial target dosage of 100 mg at bedtime. The psychiatrist explained to Ms. A that it might take 4 to 6 weeks to gauge the medication’s efficacy.

Psychoeducation addressed the importance of stress reduction, prioritizing commitments, and setting limits on other people’s expectations. The door was left open to future psychotherapeutic exploration of past cumulative stressors.

Because antidepressants may provide an analgesic effect,^6,14 they are often used to treat affective symptoms in chronic pain. Headache and neuralgia tend to respond to antidepressants more robustly than do arthritis and low-back pain. Although some patients respond to low-dose antidepressants, a definitive trial requires full doses for 6 to 8 weeks (Table 2).

Matching a patient’s symptoms with medication side effects is useful when choosing antidepressants (Table 3). So-called “adverse” effects may have a corresponding benefit, depending on the clinical presentation. For example, a moreactivating antidepressant—such as the selective serotonin reuptake inhibitor (SSRI) fluoxetine—may help a patient with fatigue, whereas a moresedating agent—such as a tricyclic antidepressant (TCA) or mirtazapine—may improve sleep for a patient with insomnia.

Psychosocial therapies such as cognitive-behavioral therapy (CBT) or relaxation training (Table 4) may help patients with chronic pain to:

• process covert emotions such as fear and anger as well as guilt, loss, and disability
• reduce somatic preoccupation that is aggravating the pain
• adhere to treatment.

Evidence strongly supports using relaxation techniques to reduce chronic pain in many medical conditions and hypnosis to ameliorate cancer pain. CBT and biofeedback appear moderately effective in relieving chronic pain.¹⁵ CBT is significantly more effective than waiting list control conditions for relieving chronic nonheadache pain in measures of pain experience, mood/affect, cognitive coping and appraisal, pain behavior and activity level, and social role functioning.¹⁶

Pain and opioid medications can impair concentration and affective processing, so initial psychotherapy may need to be supportive while you provide other treatments and simplify medication regimens. Eventually the patient may be ready to address underlying issues that may be contributing to the pain syndrome, such as a history of abuse. However, it is important to address this potentially destabilizing subject only after carefully gauging a patient’s defenses and readiness.

Case continued: A bump in the road

The psychiatrist saw Ms. A 18 months later. Interim history revealed that her pain and mood improved on nortriptyline, 100 mg at bedtime. When she stopped taking nortriptyline 5 months earlier, her neck pain increased and she experienced a “deep blue mood.” Her physician restarted the nortriptyline.

At follow up, Ms. A reported no depressive symptoms and very little neck pain. The psychiatrist discussed with her depression’s relapse rate and the importance of continuing antidepressant therapy. As Ms. A was feeling much better and functioning normally, the psychiatrist decided additional psychotherapeutic intervention was not necessary.

Antidepressant options

TCAs provide analgesia via descending regulatory pathways by inhibiting serotonin and norepinephrine reuptake.¹⁷ When using TCAs for chronic pain, start with 10 to 25 mg at bedtime and increase by 10 to 25 mg every 3 to 7 days as tolerated. Increase incrementally until the pain responds or to the full antidepressant dosage (Table 2). Drug levels (when available) can help you provide an appropriate trial and monitor the patient’s adherence.

If the pain does not respond after 6 to 8 weeks, consider switching to another dual-action agent such as venlafaxine or to an SSRI.

SNRIs. Venlafaxine is a serotonin and norepineph-rine reuptake inhibitor (SNRI) with less-troublesome side effects than TCAs. It is structurally similar to tramadol¹⁸ and has combined serotonin and norepinephrine inhibition at dosages >75 mg/d. Although venlafaxine is not indicated for chronic pain, some studies have suggested possible benefits, including long-term analgesia, reduced polyneuropathic pain, and migraine prophylaxis.^19-21 Venlafaxine may be a reasonable first or second choice for treating depression in patients with chronic pain, especially headache.¹⁴

Duloxetine—another SNRI—awaits FDA approval. Some studies have suggested that duloxetine improves painful physical symptoms as well as mood and functioning in major depression.²²

SSRIs may be effective for certain types of pain, but the evidence is conflicting. Results of 41controlled trials support TCAs’ analgesic efficacy for neuropathic pain, headache, and central and post-stroke pain, whereas SSRIs’ analgesic efficacy varies from study to study. Comparisons of TCAs and SSRIs as analgesics uniformly show TCAs to be more effective, with the SSRIs often showing no analgesic effect.

Of three controlled trials of SSRIs for diabetic neuropathy, one showed fluoxetine similar to placebo, and two smaller studies showed paroxetine and citalopram more effective than placebo. Fluoxetine has shown analgesic effect for fibromyalgia in one study, but no effect in another. Citalopram showed no analgesic effect for fibromyalgia in another study.²³

A prospective, double-blind study comparing fluoxetine, sertraline, paroxetine, and venlafaxine for migraines reported moderate to significant improvement in less than one-half of SSRI-treated patients vs two-thirds of venlafaxine-treated patients.²¹ SSRIs are no longer recognized by the International Headache Society as primary preventative medications for migraine.

Fluoxetine may help chronic daily headache, and paroxetine and citalopram may be useful for diabetic neuropathy. However, one cannot generalize that all SSRIs are similarly effective as analgesics.¹⁴

SSRIs have fewer side effects than TCAs and are less dangerous in overdose. In general, however, SSRIs are a second-line treatment for pain, to be used when dual-action agents pose disadvantageous side effects (Table 3) or have been poorly tolerated or ineffective.

Table 3

Antidepressant side effects:
Limitations and potential benefits in chronic pain

Table 4

How psychosocial therapies can help treat chronic pain and depression

Monoamine oxidase inhibitors (MAOIs) may have some efficacy for neuropathy and headache, but the need for a tyramine-free diet and potential for drug-drug interactions limit their usefulness. Co-administering an MAOI and meperidine is always contraindicated, as this combination can produce fever, delirium, seizures, circulatory collapse, and death. Similarly, avoid using an MAOI with any other antidepressant.

Others. Evidence is very limited on using other antidepressants such as trazodone, nefazodone, bupropion, and mirtazapine in chronic pain:

• Trazodone may help pediatric migraine, but it is not a consistent analgesic and may not be well-tolerated.
• Case reports suggest bupropion may help with headaches and chronic low-back pain.¹⁴
• Mirtazapine and trazodone may be useful adjuncts for treating insomnia in depressed patients with chronic pain.

Other options

Anticonvulsants appear useful for neuropathic pain and are appropriate for chronic pain patients who cannot tolerate TCAs.²⁴ Like TCAs, anticonvulsants are not addictive. Unlike TCAs, anticonvulsants may help stabilize other affective illnesses that may coexist with chronic pain, including bipolar disorder, schizoaffective disorder, and impulsivity/aggression related to dementia or personality disorder.⁶ If the starting dosage is not effective within 1 week, increase gradually every 2 to 3 days to target dosages comparable to those for anticonvulsant efficacy.

Carbamazepine and gabapentin are recommended first-line medications for neuropathy. Carbamazepine is indicated for treating trigeminal neuralgia, although its cytochrome P-450 3A3/4 isoenzyme induction may reduce serum levels of acetaminophen, opioids, and oral contraceptives. Gabapentin, although not clearly beneficial for bipolar disorder, has anxiolytic effects and a benign side-effect profile, which may help patients with chronic pain.

Valproate can help prevent migraines. Clonazepam can help reduce anxiety and restless legs syndrome but may be habituating. Anticonvulsants’ common adverse effects include sedation, GI upset, dizziness, and fatigue.

Lithium has known efficacy for mood stabilization in bipolar disorder and can ameliorate cluster headaches.

Antipsychotics. Evidence is sparse on whether antipsychotics have analgesic activity. Their side effects generally limit their usefulness to treating pain in patients with psychosis or delirium.⁶

Stimulants such as dextroamphetamine and methylphenidate can be helpful adjuncts for treating depression, especially for medical inpatients who require a rapid therapeutic response. Stimulants may reduce fatigue or excessive sedation and improve concentration in patients receiving opioids for chronic pain. They also may have analgesic effects when combined with opioids. Potential adverse effects include appetite suppression, anxiety or agitation, confusion, tics, and addiction.⁶

Precautions. The muscle relaxant carisoprodol is associated with potential dependence and withdrawal. Cyclobenzaprine, another muscle relaxant, has a TCA-like structure and can be lethal in overdose. Baclofen can be useful for chronic pain related to spasticity, although psychotic depression and mania have been reported with abrupt withdrawal.⁶

Related resources

• American Academy of Pain Medicine. www.painmed.org/
• American Academy of Pain Management. www.aapainmanage.org
• Pain.com: continuing medical education for anesthesiology professionals. www.pain.com/index.cfm
• Kerns RD, Turk DC, Rudy TE. The West Haven-Yale Multidimensional Pain Inventory (WHYMPI). Pain 1985;13:345-56

Drug brand names

• Amitriptyline • Elavil
• Baclofen • Lioresal
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol
• Carisoprodol • Soma
• Celecoxib • Celebrex
• Citalopram • Celexa
• Clomipramine • Anafranil
• Clonazepam • Klonopin
• Cyclobenzaprine • Flexeril
• Desipramine • Norpramin
• Dihydrocodeine • Synalgos-DC
• Doxepin • Sinequan
• Duloxetine • Cymbalta
• Fluoxetine • Prozac
• Gabapentin • Neurontin
• Hydrocodone • Vicodin, Lortab
• Imipramine • Tofranil
• Lithium • Eskalith CR, Lithobid
• Maprotiline • Ludiomil
• Meperidine • Demerol
• Methadone • Dolophine
• Mirtazapine • Remeron
• Nefazodone • Serzone
• Nortriptyline • Pamelor
• Oxycodone • OxyContin
• Paroxetine • Paxil
• Sertraline • Zoloft
• Tizanidine • Zanaflex
• Tramadol • Ultram
• Trazodone • Desyrel
• Valproate • Depakote
• Venlafaxine • Effexor, Effexor XR

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

When a patient exhibits depressed mood, low energy, anxiety, insomnia, and low libido, do you consider major depression related to testosterone deficiency? Psychiatrists who don’t look for hypogonadism may miss a reversible cause of depression, especially in patients whose affective symptoms don’t respond to antidepressants.

Evidence is revealing how below-normal androgen levels may affect behavior and psychopathology in both men and women. This article describes:

• possible causes and effects of hypogonadism
• how to recognize and treat depression related to testosterone deficiency
• which lab tests provide the most clinically useful measures of testosterone
• potential benefits and adverse effects of testosterone replacement therapy.

Low testosterone and depression

Testosterone deficiency is particularly common in men with treatment-resistant depression. In one study, hypogonadism (total AMtestosterone contrations ≤350 ng/dL) was detected in 24 (43%) of 56 middle-aged men with treatment-resistant depression.¹

Table 1

Signs and symptoms of testosterone deficiency

Symptoms. Although most depressed patients are not hypogonadal, testosterone deficiency can cause depressed mood, low self-confidence, timidity, fearfulness, irritability, low libido, and impaired sexual function in men^1-6 and most likely in women.⁷

Conversely, robust androgen secretion usually promotes good mood, self-confidence, boldness, dominant behavior, and strong libido. Men’s normally higher testosterone levels may relate to this sex’s lower frequency of depression and generally more violent aggression, compared with women.

Increased male aggression is associated with elevated gonadal steroid levels—from overelaboration of endogenous hormone or, more commonly, use of exogenous anabolic steroids.⁸ Less well-appreciated is that testosterone deficiency in men is frequently associated with irritability,⁹ particularly in response to stress. Correcting testosterone deficiency can improve control of hostile feelings and lead to higher self-esteem and less impulsivity.²

In general, correcting hypogonadism improves mood in men,^10,11 including those with refractory depression.^1,12

Depression in women. Evidence is conflicting and limited on a possible link between testosterone deficiency and depression in women. Psychological well-being in postmenopausal women given exogenous estrogens appears to improve when low-dose testosterone is added. In a recent placebo-controlled trial, testosterone cream, 10 mg/d—sufficient to bring total testosterone to the upper normal range—significantly improved mood in premenopausal women with low libido.¹³

Diagnosing hypogonadism

Hypogonadism is usually diagnosed by clinical and biochemical findings. Testosterone deficiency’s common signs and symptoms are shown in Table 1. Treated diabetes and obesity are significantly related to testosterone deficiency, as are—to a lesser extent—headaches, age >60, not smoking, treated asthma, low dominance rating, and sleeping <5 hr/night.¹⁴

Laboratory evaluation. Measuring total serum testosterone concentrations in blood withdrawn before 9 AMis a useful initial screen for testosterone deficiency. Circulating testosterone concentrations show diurnal variation in both sexes, with higher levels in early morning—typically 7 to 8 AM—and lowest levels in the evening—typically 7 to 8 PM. Morning concentrations of serum and salivary testosterone decline an average 50% to 60% from zenith to nadir.

Box

Total testosterone includes protein-bound and unbound testosterone and is a good measure of testosterone synthesis (Box).¹⁵ Normal circulating total testosterone levels are:

• 325 to 1,000 ng/dL in men
• 25 to 90 ng/dL in women (approximately 10% of male levels).

Testosterone assays are usually insensitive in the lower concentration ranges. This makes establishing testosterone deficiency difficult in women.

When total testosterone level is equivocal or low, repeat total testosterone levels once or twice and measure free testosterone, which is the biologically active form. More than 95% of circulating testosterone is bound to plasma proteins, including SHBG and albumin. Also measure free testosterone during the initial screen when you suspect testosterone deficiency.

In cycling women, sex hormone concentrations spike during ovulation and are low when the follicular phase begins. Although longitudinal evaluation is more accurate, the more practical crosssectional screen (AMblood) in the late follicular or late luteal phase is usually adequate.

Evaluating women taking oral contraceptives is biochemically straightforward, as exogenous estrogen suppresses ovarian sex hormone production and induces steady testosterone concentrations.

Postmenopausal women can be screened for sex hormone concentrations on virtually any morning, although perimenopausal women (within 5 years of last menstrual period) are, like premenopausal women, best studied longitudinally. DHEA and DHEA-S concentrations are perhaps more important to measure in women than in men because these sex steroids are responsible for a comparatively much larger component of circulating testosterone in women.

Follow-up tests. If testosterone deficiency is established, measure circulating pituitary hormones LH, FSH, and prolactin to determine if hypogolnadism is primary (gonadal) or secondary to another abnormality (of the brain or pituitary):

• Elevated LH and/or FSH levels are seen in primary hypogonadism, as the pituitary attempts to compensate for poorly functioning or sluggish gonads by increasing their stimulation.
• Diminished or inappropriately normal LH levels during testosterone deficiency (when high levels should be seen) are consistent with central or secondary hypogonadism.
• A combination of primary and secondary hypogonadism is common with advanced age.

Measure serum prolactin concentrations when evaluating hypogonadism because hyperprolactinemia is a common cause.

If the patient is testosterone-deficient, also assess other endocrine systems. If one fails or becomes inflamed, other glands or hormone systems often show insufficiency or inflammation as well, perhaps because of a common pathologic process. Circulating testosterone levels may be normal or elevated in testosterone insensitivity or hyposensitivity syndromes.

Correcting deficiency

Testosterone deficiency can often be corrected without using androgens, such as by changing or supplementing a medication.

Hyperprolactinemia is a common cause of central hypogonadism and testosterone deficiency in psychiatric patients, often as an adverse effect of psychotropics (particularly antipsychotics). Hyperprolactinemia suppresses GnRH and, in turn, LH and gonadal synthesis of testosterone. Hyperprolactinemia depresses libido and causes infertility in both sexes and amenorrhea in women.

Medication changes can usually correct psychotropic-induced hyperprolactinemia. Elevated prolactin levels from other causes (such as a pituitary prolactinoma) usually respond to dopamine agonists such as bromocriptine or cabergoline.

Zinc deficiency can lower testosterone levels. Zinc is highly enriched in the testes and prostate, where it accumulates via a zinc uptake system. The cerebral cortex is also zinc-enriched.

Zinc’s recommended daily allowance (RDA) is 15 mg for men and 12 mg for women. Mild zinc deficiency is common, affecting, for example, about 30% of healthy older men in Detroit¹⁶ and many depressed patients.¹⁷

Remarkably, dietary zinc restriction (to one-third of the RDA) in healthy young men reduces serum testosterone levels by 75% after 5 to 6 months. Conversely, giving a zinc supplement, 30 mg/d, to marginally zinc-deficient older men nearly doubled their serum testosterone concentrations after 6 months.¹⁸

Because serum zinc concentrations do not reliably reflect zinc status, the most expedient clinical approach is to supplement with the RDA—found in widely available multivitamins. Zinc is generally considered low-risk for toxicity, although high doses should be avoided. Much is unknown about zinc’s role in the CNS, where it apparently can be neuroprotective or neurotoxic.

Androgen suppressants. Cholesterol-lowering agents—whether they inhibit cholesterol biosynthesis or absorption—can sometimes lower serum androgen levels. Included are antihyperlipidemic pharmaceuticals and plant sterols that compete with cholesterol for gut absorption. Plant sterols such as beta-sitosterol are marketed as cholesterol-lowering food supplements.

Volatile and fatty oils of the saw palmetto berry (Seranoa repens or Sabal serrulata)—a frequently used over-the-counter phytotherapy for benign prostatic hypertrophy—have antiandrogen properties. They inhibit 5-alpha reductase types I and II, reducing testosterone’s conversion to dihydrotestosterone.¹⁹ Flaxseed oil (linseed oil), another over-the-counter herbal supplement, also may alter testosterone levels.

Table 2

Recommended testosterone-replacement preparations

Exogenous glucocorticoids suppress DHEA release by negative feedback suppression of adrenocorticotropic hormone (ACTH) at the anterior pituitary. To protect against sex hormone deficiency, give DHEA in replacement doses whenever more than a few glucocorticoid doses are given. This applies particularly to postmenopausal women, in whom DHEA is the major source of circulating androgens.

Testosterone replacement

Preliminary data suggest that correcting testosterone deficiency in depressed men can have an antidepressant effect, especially in men who respond inadequately to standard antidepressants. Moreover, like antidepressants, testosterone replacement therapy can induce hypomania or mania in some individuals.

Depression and/or anxiety associated with sustained, irreversible serum testosterone deficiency—usually with other signs of testosterone deficiency (Table 1)—is the major psychiatric indication for testosterone replacement. Borderline biochemical testosterone deficiency and psychiatric symptoms in a “treatment-resistant” patient—especially one at risk for suicide—may justify an empirical testosterone replacement trial. Do not continue such a trial indefinitely without compelling reasons, however, because gonadal function recovery can be delayed for months after even a 12-week testosterone trial.²⁰

Recommended agents for testosterone replacement are shown in Table 2. In men, testosterone preparations are normally used to increase testosterone levels. In women, I prescribe DHEA (discussed below). In young men and women with secondary hypogonadism, pulsatile use of gonadotropins may be necessary to induce spermatogenesis or ovulation—interventions outside the scope of psychiatric practice.

Contraindications to androgen replacement include hyperandrogenism, prostate cancer, antisocial personality, current mania, pedophilia, hypersexuality, and any psychiatric syndrome characterized by violent or predatory behavior. Pregnant patients (or women without a reliable birth control method) should not receive testosterone. Use caution when replacing androgens in patients with benign prostatic hypertrophy, hypomania, or a history of mania or hypomania.

An antidepressant response to adequate exogenous testosterone (enough to raise free testosterone levels to mid-normal range) is generally seen within 4 weeks. If psychological improvement is not observed, testosterone replacement may still prove beneficial if reversing hypogonadism improves the efficacy of subsequent antidepressants.

Dosage forms for men. Transdermal testosterone patches are normally applied to clean, dry skin on the upper arms, abdomen, thigh, or back and rotated among sites to avoid dermal irritation. When the nonscrotal patch is applied at night, testosterone concentrations mimic the circadian pattern seen in young men without causing supraphysiologic transients.²¹

Testosterone gel is applied every morning—also in a rotating manner—to clean, dry, intact skin and allowed to dry. Absorption is rapid, with measurable testosterone increases within 30 minutes. Approximately 10% of the testosterone is absorbed, delivering 5 to 10 mg/d into the circulation after 5 to 10 grams of gel (containing 50 to 100 mg of testosterone) is applied. Steady-state concentrations are achieved within 2 to 3 days, so dosages can be adjusted quickly.

Some patients regard 10 grams of gel as too messy to apply comfortably. Testosterone gel residuals can be washed from the skin with soap and water. Prolonged coated-skin contact with another person, such as a sex partner, can increase testosterone concentrations in the untreated individual.

Oral testosterone is absorbed poorly (often requiring high dosages) and cleared rapidly (half-life: 10 to 100 minutes). Only 10-mg capsules of methyltestosterone preparations are readily available—a dose too small for most men and too large for women. Many pharmacists can formulate other dosages for individual patients. Twice-daily doses are often used. Gum irritation and altered taste can occur when using buccal mucoadhesive testosterone.

Oil-based testosterone injections (such as IM testosteroneenanthate) are absorbedslowly and cannot reproduce normal circadian testosterone rhythms and concentrations. In some cases, however, the long-acting effectsof IM testosteroneare beneficial.

DHEA acutely increases testosterone and estrogens in both men and women after a single physiologic dose. During maintenance DHEA replacement, however, clinically significant increases in both sex hormones are seen only in women. DHEA is preferred to increase testosterone levels in women, as it is converted to appropriate proportions of androgens and estrogens by endogenous steroidogenic enzymes.

Table 3

Potential adverse effects of testosterone replacement therapy

DHEA, which occurs in yams, is available over-the-counter as a “food supplement” or “nutritional supplement.” However, many of these preparations, which are not regulated by the FDA, are unreliable because of poor quality control.²²

Aromatase inhibitors were developed as antibreastcancer agents but also may treat testosterone deficiency. Testosterone administration increases circulating estrogens because testosterone is metabolized by the enzyme aromatase to estradiol. Aromatase inhibitors may prevent excessive estradiol levels—and associated adverse effects, such as gynecomastia—that are sometimes seen during testosterone replacement therapy in men. Available aromatase inhibitors include anastrozole, exemestane, and letrozole.

Potential adverse effects

Short-term testosterone replacement is generally low-risk. Acne is the most common adverse effect (Table 3).

The incidence of adverse events increases as testosterone concentrations are elevated above the normal range. For example, about 5% of men experience a manic or hypomanic arousal within 2 to 6 weeks of induced supraphysiologic testosterone levels.⁸

Gonadal suppression. Exogenous testosterone (or high-dose DHEA) suppresses endogenous gonadal function in men and premenopausal women. When a sustained course of exogenous androgens is discontinued, gonadal suppression usually does not reverse completely for several months or longer.

Prostatic hypertrophy, commonly considered to be testosterone driven, may be a risk of testosterone replacement therapy. Emergent urinary retention during testosterone replacement therapy has been reported, so use caution when giving testosterone to men with prostatic hypertrophy.

Barring evidence to the contrary, testosterone therapy is contraindicated in patients with prostate cancer. Baseline and post-treatment prostate-specific antigen measures are recommended.

Other risks in men. Men occasionally develop gynecomastia during testosterone replacement, perhaps because of testosterone aromatization to estradiol. Beyond increased hematocrit levels and associated problems, testosterone’s cardiovascular risks are unclear. Testosterone deficiency also has been linked to increased atherosclerosis risk in older men.²³

Risks in women. Overtreating women with testosterone (DHEA) can promote hirsutism (including facial hair), loss of hair on scalp, voice lowering, clitoromegaly, breast regression, and muscle hypertrophy.

Related resources

• Daly RC, Su T-P, Schmidt PJ, et al. Cerebrospinal fluid and behavioral changes after methyltestosterone administration. Arch Gen Psychiatry 2001;58:172-7.
• Davis S. Testosterone deficiency in women.J Reprod Med2 001; 46(3 suppl):291-6.
• Rohr UD. The impact of testosterone imbalance on depression and women’s health. Maturitas 2002;41(1 suppl):S25-S46.
• Mantzoros CS, Georgiadis EI. Contribution of dihydrotestosterone to male sexual behaviour. BMJ 1995;310:1289-91.

Drug brand names

• Methyltestosterone (oral) • Android, Methitest, Testred, Virilon
• Testosterone (buccal) • Striant
• Testosterone (gel) • AndroGel, Testim
• Testosterone (transdermal) • Androderm, Testoderm
• Testosterone enanthate (IM injection) • Delatestryl

Disclosure

Dr. Geracioti reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

When a patient exhibits depressed mood, low energy, anxiety, insomnia, and low libido, do you consider major depression related to testosterone deficiency? Psychiatrists who don’t look for hypogonadism may miss a reversible cause of depression, especially in patients whose affective symptoms don’t respond to antidepressants.

Evidence is revealing how below-normal androgen levels may affect behavior and psychopathology in both men and women. This article describes:

• possible causes and effects of hypogonadism
• how to recognize and treat depression related to testosterone deficiency
• which lab tests provide the most clinically useful measures of testosterone
• potential benefits and adverse effects of testosterone replacement therapy.

Low testosterone and depression

Testosterone deficiency is particularly common in men with treatment-resistant depression. In one study, hypogonadism (total AMtestosterone contrations ≤350 ng/dL) was detected in 24 (43%) of 56 middle-aged men with treatment-resistant depression.¹

Table 1

Signs and symptoms of testosterone deficiency

Symptoms. Although most depressed patients are not hypogonadal, testosterone deficiency can cause depressed mood, low self-confidence, timidity, fearfulness, irritability, low libido, and impaired sexual function in men^1-6 and most likely in women.⁷

Conversely, robust androgen secretion usually promotes good mood, self-confidence, boldness, dominant behavior, and strong libido. Men’s normally higher testosterone levels may relate to this sex’s lower frequency of depression and generally more violent aggression, compared with women.

Increased male aggression is associated with elevated gonadal steroid levels—from overelaboration of endogenous hormone or, more commonly, use of exogenous anabolic steroids.⁸ Less well-appreciated is that testosterone deficiency in men is frequently associated with irritability,⁹ particularly in response to stress. Correcting testosterone deficiency can improve control of hostile feelings and lead to higher self-esteem and less impulsivity.²

In general, correcting hypogonadism improves mood in men,^10,11 including those with refractory depression.^1,12

Depression in women. Evidence is conflicting and limited on a possible link between testosterone deficiency and depression in women. Psychological well-being in postmenopausal women given exogenous estrogens appears to improve when low-dose testosterone is added. In a recent placebo-controlled trial, testosterone cream, 10 mg/d—sufficient to bring total testosterone to the upper normal range—significantly improved mood in premenopausal women with low libido.¹³

Diagnosing hypogonadism

Hypogonadism is usually diagnosed by clinical and biochemical findings. Testosterone deficiency’s common signs and symptoms are shown in Table 1. Treated diabetes and obesity are significantly related to testosterone deficiency, as are—to a lesser extent—headaches, age >60, not smoking, treated asthma, low dominance rating, and sleeping <5 hr/night.¹⁴

Laboratory evaluation. Measuring total serum testosterone concentrations in blood withdrawn before 9 AMis a useful initial screen for testosterone deficiency. Circulating testosterone concentrations show diurnal variation in both sexes, with higher levels in early morning—typically 7 to 8 AM—and lowest levels in the evening—typically 7 to 8 PM. Morning concentrations of serum and salivary testosterone decline an average 50% to 60% from zenith to nadir.

Box

Total testosterone includes protein-bound and unbound testosterone and is a good measure of testosterone synthesis (Box).¹⁵ Normal circulating total testosterone levels are:

• 325 to 1,000 ng/dL in men
• 25 to 90 ng/dL in women (approximately 10% of male levels).

Testosterone assays are usually insensitive in the lower concentration ranges. This makes establishing testosterone deficiency difficult in women.

When total testosterone level is equivocal or low, repeat total testosterone levels once or twice and measure free testosterone, which is the biologically active form. More than 95% of circulating testosterone is bound to plasma proteins, including SHBG and albumin. Also measure free testosterone during the initial screen when you suspect testosterone deficiency.

In cycling women, sex hormone concentrations spike during ovulation and are low when the follicular phase begins. Although longitudinal evaluation is more accurate, the more practical crosssectional screen (AMblood) in the late follicular or late luteal phase is usually adequate.

Evaluating women taking oral contraceptives is biochemically straightforward, as exogenous estrogen suppresses ovarian sex hormone production and induces steady testosterone concentrations.

Postmenopausal women can be screened for sex hormone concentrations on virtually any morning, although perimenopausal women (within 5 years of last menstrual period) are, like premenopausal women, best studied longitudinally. DHEA and DHEA-S concentrations are perhaps more important to measure in women than in men because these sex steroids are responsible for a comparatively much larger component of circulating testosterone in women.

Follow-up tests. If testosterone deficiency is established, measure circulating pituitary hormones LH, FSH, and prolactin to determine if hypogolnadism is primary (gonadal) or secondary to another abnormality (of the brain or pituitary):

• Elevated LH and/or FSH levels are seen in primary hypogonadism, as the pituitary attempts to compensate for poorly functioning or sluggish gonads by increasing their stimulation.
• Diminished or inappropriately normal LH levels during testosterone deficiency (when high levels should be seen) are consistent with central or secondary hypogonadism.
• A combination of primary and secondary hypogonadism is common with advanced age.

Measure serum prolactin concentrations when evaluating hypogonadism because hyperprolactinemia is a common cause.

If the patient is testosterone-deficient, also assess other endocrine systems. If one fails or becomes inflamed, other glands or hormone systems often show insufficiency or inflammation as well, perhaps because of a common pathologic process. Circulating testosterone levels may be normal or elevated in testosterone insensitivity or hyposensitivity syndromes.

Correcting deficiency

Testosterone deficiency can often be corrected without using androgens, such as by changing or supplementing a medication.

Hyperprolactinemia is a common cause of central hypogonadism and testosterone deficiency in psychiatric patients, often as an adverse effect of psychotropics (particularly antipsychotics). Hyperprolactinemia suppresses GnRH and, in turn, LH and gonadal synthesis of testosterone. Hyperprolactinemia depresses libido and causes infertility in both sexes and amenorrhea in women.

Medication changes can usually correct psychotropic-induced hyperprolactinemia. Elevated prolactin levels from other causes (such as a pituitary prolactinoma) usually respond to dopamine agonists such as bromocriptine or cabergoline.

Zinc deficiency can lower testosterone levels. Zinc is highly enriched in the testes and prostate, where it accumulates via a zinc uptake system. The cerebral cortex is also zinc-enriched.

Zinc’s recommended daily allowance (RDA) is 15 mg for men and 12 mg for women. Mild zinc deficiency is common, affecting, for example, about 30% of healthy older men in Detroit¹⁶ and many depressed patients.¹⁷

Remarkably, dietary zinc restriction (to one-third of the RDA) in healthy young men reduces serum testosterone levels by 75% after 5 to 6 months. Conversely, giving a zinc supplement, 30 mg/d, to marginally zinc-deficient older men nearly doubled their serum testosterone concentrations after 6 months.¹⁸

Because serum zinc concentrations do not reliably reflect zinc status, the most expedient clinical approach is to supplement with the RDA—found in widely available multivitamins. Zinc is generally considered low-risk for toxicity, although high doses should be avoided. Much is unknown about zinc’s role in the CNS, where it apparently can be neuroprotective or neurotoxic.

Androgen suppressants. Cholesterol-lowering agents—whether they inhibit cholesterol biosynthesis or absorption—can sometimes lower serum androgen levels. Included are antihyperlipidemic pharmaceuticals and plant sterols that compete with cholesterol for gut absorption. Plant sterols such as beta-sitosterol are marketed as cholesterol-lowering food supplements.

Volatile and fatty oils of the saw palmetto berry (Seranoa repens or Sabal serrulata)—a frequently used over-the-counter phytotherapy for benign prostatic hypertrophy—have antiandrogen properties. They inhibit 5-alpha reductase types I and II, reducing testosterone’s conversion to dihydrotestosterone.¹⁹ Flaxseed oil (linseed oil), another over-the-counter herbal supplement, also may alter testosterone levels.

Table 2

Recommended testosterone-replacement preparations

Exogenous glucocorticoids suppress DHEA release by negative feedback suppression of adrenocorticotropic hormone (ACTH) at the anterior pituitary. To protect against sex hormone deficiency, give DHEA in replacement doses whenever more than a few glucocorticoid doses are given. This applies particularly to postmenopausal women, in whom DHEA is the major source of circulating androgens.

Testosterone replacement

Preliminary data suggest that correcting testosterone deficiency in depressed men can have an antidepressant effect, especially in men who respond inadequately to standard antidepressants. Moreover, like antidepressants, testosterone replacement therapy can induce hypomania or mania in some individuals.

Depression and/or anxiety associated with sustained, irreversible serum testosterone deficiency—usually with other signs of testosterone deficiency (Table 1)—is the major psychiatric indication for testosterone replacement. Borderline biochemical testosterone deficiency and psychiatric symptoms in a “treatment-resistant” patient—especially one at risk for suicide—may justify an empirical testosterone replacement trial. Do not continue such a trial indefinitely without compelling reasons, however, because gonadal function recovery can be delayed for months after even a 12-week testosterone trial.²⁰

Recommended agents for testosterone replacement are shown in Table 2. In men, testosterone preparations are normally used to increase testosterone levels. In women, I prescribe DHEA (discussed below). In young men and women with secondary hypogonadism, pulsatile use of gonadotropins may be necessary to induce spermatogenesis or ovulation—interventions outside the scope of psychiatric practice.

Contraindications to androgen replacement include hyperandrogenism, prostate cancer, antisocial personality, current mania, pedophilia, hypersexuality, and any psychiatric syndrome characterized by violent or predatory behavior. Pregnant patients (or women without a reliable birth control method) should not receive testosterone. Use caution when replacing androgens in patients with benign prostatic hypertrophy, hypomania, or a history of mania or hypomania.

An antidepressant response to adequate exogenous testosterone (enough to raise free testosterone levels to mid-normal range) is generally seen within 4 weeks. If psychological improvement is not observed, testosterone replacement may still prove beneficial if reversing hypogonadism improves the efficacy of subsequent antidepressants.

Dosage forms for men. Transdermal testosterone patches are normally applied to clean, dry skin on the upper arms, abdomen, thigh, or back and rotated among sites to avoid dermal irritation. When the nonscrotal patch is applied at night, testosterone concentrations mimic the circadian pattern seen in young men without causing supraphysiologic transients.²¹

Testosterone gel is applied every morning—also in a rotating manner—to clean, dry, intact skin and allowed to dry. Absorption is rapid, with measurable testosterone increases within 30 minutes. Approximately 10% of the testosterone is absorbed, delivering 5 to 10 mg/d into the circulation after 5 to 10 grams of gel (containing 50 to 100 mg of testosterone) is applied. Steady-state concentrations are achieved within 2 to 3 days, so dosages can be adjusted quickly.

Some patients regard 10 grams of gel as too messy to apply comfortably. Testosterone gel residuals can be washed from the skin with soap and water. Prolonged coated-skin contact with another person, such as a sex partner, can increase testosterone concentrations in the untreated individual.

Oral testosterone is absorbed poorly (often requiring high dosages) and cleared rapidly (half-life: 10 to 100 minutes). Only 10-mg capsules of methyltestosterone preparations are readily available—a dose too small for most men and too large for women. Many pharmacists can formulate other dosages for individual patients. Twice-daily doses are often used. Gum irritation and altered taste can occur when using buccal mucoadhesive testosterone.

Oil-based testosterone injections (such as IM testosteroneenanthate) are absorbedslowly and cannot reproduce normal circadian testosterone rhythms and concentrations. In some cases, however, the long-acting effectsof IM testosteroneare beneficial.

DHEA acutely increases testosterone and estrogens in both men and women after a single physiologic dose. During maintenance DHEA replacement, however, clinically significant increases in both sex hormones are seen only in women. DHEA is preferred to increase testosterone levels in women, as it is converted to appropriate proportions of androgens and estrogens by endogenous steroidogenic enzymes.

Table 3

Potential adverse effects of testosterone replacement therapy

DHEA, which occurs in yams, is available over-the-counter as a “food supplement” or “nutritional supplement.” However, many of these preparations, which are not regulated by the FDA, are unreliable because of poor quality control.²²

Aromatase inhibitors were developed as antibreastcancer agents but also may treat testosterone deficiency. Testosterone administration increases circulating estrogens because testosterone is metabolized by the enzyme aromatase to estradiol. Aromatase inhibitors may prevent excessive estradiol levels—and associated adverse effects, such as gynecomastia—that are sometimes seen during testosterone replacement therapy in men. Available aromatase inhibitors include anastrozole, exemestane, and letrozole.

Potential adverse effects

Short-term testosterone replacement is generally low-risk. Acne is the most common adverse effect (Table 3).

The incidence of adverse events increases as testosterone concentrations are elevated above the normal range. For example, about 5% of men experience a manic or hypomanic arousal within 2 to 6 weeks of induced supraphysiologic testosterone levels.⁸

Gonadal suppression. Exogenous testosterone (or high-dose DHEA) suppresses endogenous gonadal function in men and premenopausal women. When a sustained course of exogenous androgens is discontinued, gonadal suppression usually does not reverse completely for several months or longer.

Prostatic hypertrophy, commonly considered to be testosterone driven, may be a risk of testosterone replacement therapy. Emergent urinary retention during testosterone replacement therapy has been reported, so use caution when giving testosterone to men with prostatic hypertrophy.

Barring evidence to the contrary, testosterone therapy is contraindicated in patients with prostate cancer. Baseline and post-treatment prostate-specific antigen measures are recommended.

Other risks in men. Men occasionally develop gynecomastia during testosterone replacement, perhaps because of testosterone aromatization to estradiol. Beyond increased hematocrit levels and associated problems, testosterone’s cardiovascular risks are unclear. Testosterone deficiency also has been linked to increased atherosclerosis risk in older men.²³

Risks in women. Overtreating women with testosterone (DHEA) can promote hirsutism (including facial hair), loss of hair on scalp, voice lowering, clitoromegaly, breast regression, and muscle hypertrophy.

Related resources

• Daly RC, Su T-P, Schmidt PJ, et al. Cerebrospinal fluid and behavioral changes after methyltestosterone administration. Arch Gen Psychiatry 2001;58:172-7.
• Davis S. Testosterone deficiency in women.J Reprod Med2 001; 46(3 suppl):291-6.
• Rohr UD. The impact of testosterone imbalance on depression and women’s health. Maturitas 2002;41(1 suppl):S25-S46.
• Mantzoros CS, Georgiadis EI. Contribution of dihydrotestosterone to male sexual behaviour. BMJ 1995;310:1289-91.

Drug brand names

• Methyltestosterone (oral) • Android, Methitest, Testred, Virilon
• Testosterone (buccal) • Striant
• Testosterone (gel) • AndroGel, Testim
• Testosterone (transdermal) • Androderm, Testoderm
• Testosterone enanthate (IM injection) • Delatestryl

Disclosure

Dr. Geracioti reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

When a patient exhibits depressed mood, low energy, anxiety, insomnia, and low libido, do you consider major depression related to testosterone deficiency? Psychiatrists who don’t look for hypogonadism may miss a reversible cause of depression, especially in patients whose affective symptoms don’t respond to antidepressants.

Evidence is revealing how below-normal androgen levels may affect behavior and psychopathology in both men and women. This article describes:

• possible causes and effects of hypogonadism
• how to recognize and treat depression related to testosterone deficiency
• which lab tests provide the most clinically useful measures of testosterone
• potential benefits and adverse effects of testosterone replacement therapy.

Low testosterone and depression

Testosterone deficiency is particularly common in men with treatment-resistant depression. In one study, hypogonadism (total AMtestosterone contrations ≤350 ng/dL) was detected in 24 (43%) of 56 middle-aged men with treatment-resistant depression.¹

Table 1

Signs and symptoms of testosterone deficiency

Symptoms. Although most depressed patients are not hypogonadal, testosterone deficiency can cause depressed mood, low self-confidence, timidity, fearfulness, irritability, low libido, and impaired sexual function in men^1-6 and most likely in women.⁷

Conversely, robust androgen secretion usually promotes good mood, self-confidence, boldness, dominant behavior, and strong libido. Men’s normally higher testosterone levels may relate to this sex’s lower frequency of depression and generally more violent aggression, compared with women.

Increased male aggression is associated with elevated gonadal steroid levels—from overelaboration of endogenous hormone or, more commonly, use of exogenous anabolic steroids.⁸ Less well-appreciated is that testosterone deficiency in men is frequently associated with irritability,⁹ particularly in response to stress. Correcting testosterone deficiency can improve control of hostile feelings and lead to higher self-esteem and less impulsivity.²

In general, correcting hypogonadism improves mood in men,^10,11 including those with refractory depression.^1,12

Depression in women. Evidence is conflicting and limited on a possible link between testosterone deficiency and depression in women. Psychological well-being in postmenopausal women given exogenous estrogens appears to improve when low-dose testosterone is added. In a recent placebo-controlled trial, testosterone cream, 10 mg/d—sufficient to bring total testosterone to the upper normal range—significantly improved mood in premenopausal women with low libido.¹³

Diagnosing hypogonadism

Hypogonadism is usually diagnosed by clinical and biochemical findings. Testosterone deficiency’s common signs and symptoms are shown in Table 1. Treated diabetes and obesity are significantly related to testosterone deficiency, as are—to a lesser extent—headaches, age >60, not smoking, treated asthma, low dominance rating, and sleeping <5 hr/night.¹⁴

Laboratory evaluation. Measuring total serum testosterone concentrations in blood withdrawn before 9 AMis a useful initial screen for testosterone deficiency. Circulating testosterone concentrations show diurnal variation in both sexes, with higher levels in early morning—typically 7 to 8 AM—and lowest levels in the evening—typically 7 to 8 PM. Morning concentrations of serum and salivary testosterone decline an average 50% to 60% from zenith to nadir.

Box

Total testosterone includes protein-bound and unbound testosterone and is a good measure of testosterone synthesis (Box).¹⁵ Normal circulating total testosterone levels are:

• 325 to 1,000 ng/dL in men
• 25 to 90 ng/dL in women (approximately 10% of male levels).

Testosterone assays are usually insensitive in the lower concentration ranges. This makes establishing testosterone deficiency difficult in women.

When total testosterone level is equivocal or low, repeat total testosterone levels once or twice and measure free testosterone, which is the biologically active form. More than 95% of circulating testosterone is bound to plasma proteins, including SHBG and albumin. Also measure free testosterone during the initial screen when you suspect testosterone deficiency.

In cycling women, sex hormone concentrations spike during ovulation and are low when the follicular phase begins. Although longitudinal evaluation is more accurate, the more practical crosssectional screen (AMblood) in the late follicular or late luteal phase is usually adequate.

Evaluating women taking oral contraceptives is biochemically straightforward, as exogenous estrogen suppresses ovarian sex hormone production and induces steady testosterone concentrations.

Postmenopausal women can be screened for sex hormone concentrations on virtually any morning, although perimenopausal women (within 5 years of last menstrual period) are, like premenopausal women, best studied longitudinally. DHEA and DHEA-S concentrations are perhaps more important to measure in women than in men because these sex steroids are responsible for a comparatively much larger component of circulating testosterone in women.

Follow-up tests. If testosterone deficiency is established, measure circulating pituitary hormones LH, FSH, and prolactin to determine if hypogolnadism is primary (gonadal) or secondary to another abnormality (of the brain or pituitary):

• Elevated LH and/or FSH levels are seen in primary hypogonadism, as the pituitary attempts to compensate for poorly functioning or sluggish gonads by increasing their stimulation.
• Diminished or inappropriately normal LH levels during testosterone deficiency (when high levels should be seen) are consistent with central or secondary hypogonadism.
• A combination of primary and secondary hypogonadism is common with advanced age.

Measure serum prolactin concentrations when evaluating hypogonadism because hyperprolactinemia is a common cause.

If the patient is testosterone-deficient, also assess other endocrine systems. If one fails or becomes inflamed, other glands or hormone systems often show insufficiency or inflammation as well, perhaps because of a common pathologic process. Circulating testosterone levels may be normal or elevated in testosterone insensitivity or hyposensitivity syndromes.

Correcting deficiency

Testosterone deficiency can often be corrected without using androgens, such as by changing or supplementing a medication.

Hyperprolactinemia is a common cause of central hypogonadism and testosterone deficiency in psychiatric patients, often as an adverse effect of psychotropics (particularly antipsychotics). Hyperprolactinemia suppresses GnRH and, in turn, LH and gonadal synthesis of testosterone. Hyperprolactinemia depresses libido and causes infertility in both sexes and amenorrhea in women.

Medication changes can usually correct psychotropic-induced hyperprolactinemia. Elevated prolactin levels from other causes (such as a pituitary prolactinoma) usually respond to dopamine agonists such as bromocriptine or cabergoline.

Zinc deficiency can lower testosterone levels. Zinc is highly enriched in the testes and prostate, where it accumulates via a zinc uptake system. The cerebral cortex is also zinc-enriched.

Zinc’s recommended daily allowance (RDA) is 15 mg for men and 12 mg for women. Mild zinc deficiency is common, affecting, for example, about 30% of healthy older men in Detroit¹⁶ and many depressed patients.¹⁷

Remarkably, dietary zinc restriction (to one-third of the RDA) in healthy young men reduces serum testosterone levels by 75% after 5 to 6 months. Conversely, giving a zinc supplement, 30 mg/d, to marginally zinc-deficient older men nearly doubled their serum testosterone concentrations after 6 months.¹⁸

Because serum zinc concentrations do not reliably reflect zinc status, the most expedient clinical approach is to supplement with the RDA—found in widely available multivitamins. Zinc is generally considered low-risk for toxicity, although high doses should be avoided. Much is unknown about zinc’s role in the CNS, where it apparently can be neuroprotective or neurotoxic.

Androgen suppressants. Cholesterol-lowering agents—whether they inhibit cholesterol biosynthesis or absorption—can sometimes lower serum androgen levels. Included are antihyperlipidemic pharmaceuticals and plant sterols that compete with cholesterol for gut absorption. Plant sterols such as beta-sitosterol are marketed as cholesterol-lowering food supplements.

Volatile and fatty oils of the saw palmetto berry (Seranoa repens or Sabal serrulata)—a frequently used over-the-counter phytotherapy for benign prostatic hypertrophy—have antiandrogen properties. They inhibit 5-alpha reductase types I and II, reducing testosterone’s conversion to dihydrotestosterone.¹⁹ Flaxseed oil (linseed oil), another over-the-counter herbal supplement, also may alter testosterone levels.

Table 2

Recommended testosterone-replacement preparations

Exogenous glucocorticoids suppress DHEA release by negative feedback suppression of adrenocorticotropic hormone (ACTH) at the anterior pituitary. To protect against sex hormone deficiency, give DHEA in replacement doses whenever more than a few glucocorticoid doses are given. This applies particularly to postmenopausal women, in whom DHEA is the major source of circulating androgens.

Testosterone replacement

Preliminary data suggest that correcting testosterone deficiency in depressed men can have an antidepressant effect, especially in men who respond inadequately to standard antidepressants. Moreover, like antidepressants, testosterone replacement therapy can induce hypomania or mania in some individuals.

Depression and/or anxiety associated with sustained, irreversible serum testosterone deficiency—usually with other signs of testosterone deficiency (Table 1)—is the major psychiatric indication for testosterone replacement. Borderline biochemical testosterone deficiency and psychiatric symptoms in a “treatment-resistant” patient—especially one at risk for suicide—may justify an empirical testosterone replacement trial. Do not continue such a trial indefinitely without compelling reasons, however, because gonadal function recovery can be delayed for months after even a 12-week testosterone trial.²⁰

Recommended agents for testosterone replacement are shown in Table 2. In men, testosterone preparations are normally used to increase testosterone levels. In women, I prescribe DHEA (discussed below). In young men and women with secondary hypogonadism, pulsatile use of gonadotropins may be necessary to induce spermatogenesis or ovulation—interventions outside the scope of psychiatric practice.

Contraindications to androgen replacement include hyperandrogenism, prostate cancer, antisocial personality, current mania, pedophilia, hypersexuality, and any psychiatric syndrome characterized by violent or predatory behavior. Pregnant patients (or women without a reliable birth control method) should not receive testosterone. Use caution when replacing androgens in patients with benign prostatic hypertrophy, hypomania, or a history of mania or hypomania.

An antidepressant response to adequate exogenous testosterone (enough to raise free testosterone levels to mid-normal range) is generally seen within 4 weeks. If psychological improvement is not observed, testosterone replacement may still prove beneficial if reversing hypogonadism improves the efficacy of subsequent antidepressants.

Dosage forms for men. Transdermal testosterone patches are normally applied to clean, dry skin on the upper arms, abdomen, thigh, or back and rotated among sites to avoid dermal irritation. When the nonscrotal patch is applied at night, testosterone concentrations mimic the circadian pattern seen in young men without causing supraphysiologic transients.²¹

Testosterone gel is applied every morning—also in a rotating manner—to clean, dry, intact skin and allowed to dry. Absorption is rapid, with measurable testosterone increases within 30 minutes. Approximately 10% of the testosterone is absorbed, delivering 5 to 10 mg/d into the circulation after 5 to 10 grams of gel (containing 50 to 100 mg of testosterone) is applied. Steady-state concentrations are achieved within 2 to 3 days, so dosages can be adjusted quickly.

Some patients regard 10 grams of gel as too messy to apply comfortably. Testosterone gel residuals can be washed from the skin with soap and water. Prolonged coated-skin contact with another person, such as a sex partner, can increase testosterone concentrations in the untreated individual.

Oral testosterone is absorbed poorly (often requiring high dosages) and cleared rapidly (half-life: 10 to 100 minutes). Only 10-mg capsules of methyltestosterone preparations are readily available—a dose too small for most men and too large for women. Many pharmacists can formulate other dosages for individual patients. Twice-daily doses are often used. Gum irritation and altered taste can occur when using buccal mucoadhesive testosterone.

Oil-based testosterone injections (such as IM testosteroneenanthate) are absorbedslowly and cannot reproduce normal circadian testosterone rhythms and concentrations. In some cases, however, the long-acting effectsof IM testosteroneare beneficial.

DHEA acutely increases testosterone and estrogens in both men and women after a single physiologic dose. During maintenance DHEA replacement, however, clinically significant increases in both sex hormones are seen only in women. DHEA is preferred to increase testosterone levels in women, as it is converted to appropriate proportions of androgens and estrogens by endogenous steroidogenic enzymes.

Table 3

Potential adverse effects of testosterone replacement therapy

DHEA, which occurs in yams, is available over-the-counter as a “food supplement” or “nutritional supplement.” However, many of these preparations, which are not regulated by the FDA, are unreliable because of poor quality control.²²

Aromatase inhibitors were developed as antibreastcancer agents but also may treat testosterone deficiency. Testosterone administration increases circulating estrogens because testosterone is metabolized by the enzyme aromatase to estradiol. Aromatase inhibitors may prevent excessive estradiol levels—and associated adverse effects, such as gynecomastia—that are sometimes seen during testosterone replacement therapy in men. Available aromatase inhibitors include anastrozole, exemestane, and letrozole.

Potential adverse effects

Short-term testosterone replacement is generally low-risk. Acne is the most common adverse effect (Table 3).

The incidence of adverse events increases as testosterone concentrations are elevated above the normal range. For example, about 5% of men experience a manic or hypomanic arousal within 2 to 6 weeks of induced supraphysiologic testosterone levels.⁸

Gonadal suppression. Exogenous testosterone (or high-dose DHEA) suppresses endogenous gonadal function in men and premenopausal women. When a sustained course of exogenous androgens is discontinued, gonadal suppression usually does not reverse completely for several months or longer.

Prostatic hypertrophy, commonly considered to be testosterone driven, may be a risk of testosterone replacement therapy. Emergent urinary retention during testosterone replacement therapy has been reported, so use caution when giving testosterone to men with prostatic hypertrophy.

Barring evidence to the contrary, testosterone therapy is contraindicated in patients with prostate cancer. Baseline and post-treatment prostate-specific antigen measures are recommended.

Other risks in men. Men occasionally develop gynecomastia during testosterone replacement, perhaps because of testosterone aromatization to estradiol. Beyond increased hematocrit levels and associated problems, testosterone’s cardiovascular risks are unclear. Testosterone deficiency also has been linked to increased atherosclerosis risk in older men.²³

Risks in women. Overtreating women with testosterone (DHEA) can promote hirsutism (including facial hair), loss of hair on scalp, voice lowering, clitoromegaly, breast regression, and muscle hypertrophy.

Related resources

• Daly RC, Su T-P, Schmidt PJ, et al. Cerebrospinal fluid and behavioral changes after methyltestosterone administration. Arch Gen Psychiatry 2001;58:172-7.
• Davis S. Testosterone deficiency in women.J Reprod Med2 001; 46(3 suppl):291-6.
• Rohr UD. The impact of testosterone imbalance on depression and women’s health. Maturitas 2002;41(1 suppl):S25-S46.
• Mantzoros CS, Georgiadis EI. Contribution of dihydrotestosterone to male sexual behaviour. BMJ 1995;310:1289-91.

Drug brand names

• Methyltestosterone (oral) • Android, Methitest, Testred, Virilon
• Testosterone (buccal) • Striant
• Testosterone (gel) • AndroGel, Testim
• Testosterone (transdermal) • Androderm, Testoderm
• Testosterone enanthate (IM injection) • Delatestryl

Disclosure

Dr. Geracioti reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.